%0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between α-Klotho and Deep White Matter Lesions in the Brain: A Pilot Case Control Study Using Brain MRI. %A Kuriyama, Nagato %A Ozaki, Etsuko %A Mizuno, Toshiki %A Ihara, Masafumi %A Mizuno, Shigeto %A Koyama, Teruhide %A Matsui, Daisuke %A Watanabe, Isao %A Akazawa, Kentaro %A Takeda, Kazuo %A Takada, Akihiro %A Inaba, Masaaki %A Yamada, Shinsuke %A Motoyama, Koka %A Takeshita, Wakiko %A Iwai, Komei %A Hashiguchi, Kanae %A Kobayashi, Daiki %A Kondo, Masaki %A Tamura, Aiko %A Yamada, Kei %A Nakagawa, Masanori %A Watanabe, Yoshiyuki %K Aged %K Aged, 80 and over %K Apolipoprotein E4 %K Brain %K C-Reactive Protein %K Case-Control Studies %K Cognition Disorders %K Female %K Glucuronidase %K Humans %K Image Processing, Computer-Assisted %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Pilot Projects %K Severity of Illness Index %X

BACKGROUND: The anti-aging protein, α-Klotho, may be involved in cognitive decline and has potential as a surrogate marker that reflects dementia. However, the role of α-Klotho in the brain has not been sufficiently investigated.

OBJECTIVE: Here, we investigated the association between α-Klotho and cognitive decline that is associated with cerebral deep white matter lesions (DWMLs).

METHODS: Two hundred-eighty participants (187 males and 93 females, mean age: 70.8 years old) were evaluated for DWMLs, and the Fazekas scale (Grade) was assessed following brain magnetic resonance imaging. A questionnaire concerning lifestyle and neuropsychological tests was administered, and their associations with the blood α-Klotho level were retrospectively investigated.

RESULTS: The α-Klotho level was 685.1 pg/mL in Grade 0 (68 subjects), 634.1 in G1 (134), 596.0 in G2 (62), and 571.6 in G3 (16), showing that the level significantly decreased with advanced grades. Significant correlations were noted between the α-Klotho level and higher brain function tests including the Mini-Mental State Examination and word fluency tests (p < 0.05). When a 90th percentile value of the level in the G0 group (400 pg/mL) or lower was defined as a low α-Klotho level, the odds ratio of the high-grade G3 group was 2.9 (95% confidence interval: 1.4-7.8) (after correction for age, sex, hypertension, and chronic kidney disease), which was significant.

CONCLUSION: A reduced blood α-Klotho level was correlated with grading of cerebral DWMLs and was accompanied by cognitive decline as an independent risk factor. The α-Klotho level may serve as a useful clinical index of vascular cognitive impairment.

%B J Alzheimers Dis %V 61 %P 145-155 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154273?dopt=Abstract %R 10.3233/JAD-170466 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease. %A Geijselaers, Stefan L C %A Aalten, Pauline %A Ramakers, Inez H G B %A De Deyn, Peter Paul %A Heijboer, Annemieke C %A Koek, Huiberdina L %A OldeRikkert, Marcel G M %A Papma, Janne M %A Reesink, Fransje E %A Smits, Lieke L %A Stehouwer, Coen D A %A Teunissen, Charlotte E %A Verhey, Frans R J %A van der Flier, Wiesje M %A Biessels, Geert Jan %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Brain %K Cognition Disorders %K Female %K Humans %K Insulin %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Signal Transduction %K tau Proteins %X

BACKGROUND: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).

OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.

METHODS: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.

RESULTS: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).

CONCLUSION: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

%B J Alzheimers Dis %V 61 %P 309-320 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154275?dopt=Abstract %R 10.3233/JAD-170522 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Concordance Between Cerebrospinal Fluid Biomarkers with Alzheimer's Disease Pathology Between Three Independent Assay Platforms. %A Doecke, James D %A Rembach, Alan %A Villemagne, Victor L %A Varghese, Shiji %A Rainey-Smith, Stephanie %A Sarros, Shannon %A Evered, Lisbeth A %A Fowler, Christopher J %A Pertile, Kelly K %A Rumble, Rebecca L %A Trounson, Brett %A Taddei, Kevin %A Laws, Simon M %A Macaulay, S Lance %A Bush, Ashley I %A Ellis, Kathryn A %A Martins, Ralph %A Ames, David %A Silbert, Brendan %A Vanderstichele, Hugo %A Masters, Colin L %A Darby, David G %A Li, Qiao-Xin %A Collins, Steven %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognition Disorders %K Female %K Humans %K Male %K Mental Status Schedule %K Peptide Fragments %K Positron-Emission Tomography %K ROC Curve %K tau Proteins %X

BACKGROUND: To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial.

OBJECTIVE: Assessing levels of Aβ-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aβ-amyloid (32 Aβ-amyloid-and 45 Aβ-amyloid+), as well as concordance between CSF biomarker levels and PET Aβ-amyloid imaging.

METHODS: Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging.

RESULTS: Across all three platforms, the T-tau/Aβ42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ= 0.69-0.8) as compared with Aβ42 alone (ρ= 0.66-0.75). Differences in CSF biomarker levels between the PET Aβ-amyloid-and Aβ-amyloid+ groups were strongest for the Aβ42/Aβ40 and T-tau/Aβ42 ratios (p < 0.0001); however, comparison of predictive models for PET Aβ-amyloid showed no difference between Aβ42 alone and the T-tau/Aβ42 ratio.

CONCLUSION: This study confirms strong concordance between CSF biomarkers and PET Aβ-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.

%B J Alzheimers Dis %V 61 %P 169-183 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171991?dopt=Abstract %R 10.3233/JAD-170128 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Establishing a New Screening System for Mild Cognitive Impairment and Alzheimer's Disease with Mental Rotation Tasks that Evaluate Visuospatial Function. %A Suzuki, Ayuko %A Shinozaki, Jun %A Yazawa, Shogo %A Ueki, Yoshino %A Matsukawa, Noriyuki %A Shimohama, Shun %A Nagamine, Takashi %K Aged %K Aged, 80 and over %K Agnosia %K Alzheimer Disease %K Case-Control Studies %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Early Diagnosis %K Eye Movements %K Female %K Humans %K Male %K Mental Status Schedule %K Reaction Time %K ROC Curve %X

BACKGROUND: The mental rotation task is well-known for the assessment of visuospatial function; however, it has not been used for screening of dementia patients.

OBJECTIVE: The aim of this study was to create a simple screening test for patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by focusing on non-amnestic symptoms.

METHODS: Age-matched healthy controls (age 75.3±6.8), patients with MCI (76.5±5.5), and AD (78.2±5.0) participated in this study. They carried out mental rotation tasks targeting geometric graphics or alphabetical characters with three rotating angles (0°, 90°, and 180°) and indicated the correct answer. Response accuracy and reaction time were recorded along with their eye movements using an eye tracker. To quantify their visual processing strategy, the run count ratio (RC ratio) was calculated by dividing the mean number of fixations in incorrect answers by that in correct answers.

RESULTS: AD patients showed lower accuracy and longer reaction time than controls. They also showed a significantly greater number of fixation and smaller saccade amplitude than controls, while fixation duration did not differ significantly. The RC ratio was higher for AD, followed by MCI and control groups. By setting the cut-off value to 0.47 in the 180° rotating angle task, we could differentiate MCI patients from controls with a probability of 80.0%.

CONCLUSIONS: We established a new screening system for dementia patients by evaluating visuospatial function. The RC ratio during a mental rotation task is useful for discriminating MCI patients from controls.

%B J Alzheimers Dis %V 61 %P 1653-1665 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376869?dopt=Abstract %R 10.3233/JAD-170801 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. %A Kirson, Noam Y %A Scott Andrews, J %A Desai, Urvi %A King, Sarah B %A Schonfeld, Sophie %A Birnbaum, Howard G %A Ball, Daniel E %A Kahle-Wrobleski, Kristin %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Cohort Studies %K Datasets as Topic %K Disease Progression %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Statistics, Nonparametric %K Time Factors %X

BACKGROUND: Effectiveness of Alzheimer's disease (AD) treatments may depend critically on the timeliness of intervention.

OBJECTIVE: To compare characteristics and outcomes of patients diagnosed with probable AD (prAD) based on time elapsed from first onset of cognitive decline.

METHODS: Patients with ≥1 prAD diagnosis and ≥1 follow-up visit were selected from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS; 9/2005-6/2015) and stratified based on the time between the perceived onset of cognitive decline at baseline and first prAD diagnosis (i.e., earlier versus later diagnosis). Characteristics at baseline and prAD diagnosis, clinically meaningful progression, and medication use following prAD diagnosis were compared.

RESULTS: Median time from perceived onset of cognitive decline to prAD diagnosis was 4.5 years (earlier diagnosis: ≤3.46; later diagnosis: >5.71). Earlier-diagnosed patients (n = 1,476) were younger at baseline (74.3 versus 76.3 years) and had better cognitive and functional scores than later-diagnosed patients (n = 1,474). At first prAD diagnosis, earlier-diagnosed patients had lower mean global Clinical Dementia Rating (CDR) score (0.8 versus 1.1), higher mean Mini-Mental State Examination (MMSE) (22.6 versus 20.0), and lower mean Functional Activities Questionnaire (11.6 versus 17.3). Earlier- and later-diagnosed patients experienced similar time to a decrease of ≥3 points in MMSE (median 23.2 versus 23.1 months, p = 0.83), but earlier-diagnosed patients had longer time to a CDR score of ≥2 points, and longer times to initiation of AD medication and antipsychotic agents (all p < 0.01).

CONCLUSION: Earlier prAD diagnosis in NACC data is associated with higher cognitive function and lower functional impairment at diagnosis.

%B J Alzheimers Dis %V 61 %P 295-307 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154268?dopt=Abstract %R 10.3233/JAD-170078 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Amyloid-β Deposition and Long-Term Progression in Mild Cognitive Impairment due to Alzheimer's Disease Defined with Amyloid PET Imaging. %A Hatashita, Shizuo %A Wakebe, Daichi %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Aniline Compounds %K Cognitive Dysfunction %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Positron-Emission Tomography %K Thiazoles %X

The aim was to evaluate brain amyloid-β (Aβ) deposition in patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) using amyloid PET imaging and clarify the relationship between the annual change in Aβ deposition and disease progression. Forty-eight MCI patients underwent neuropsychological assessment and amyloid PET imaging using [11C]-PIB over a follow-up of 5.7±1.5 years. Thirty-nine MCI patients who had an amyloid-positive scan were defined as MCI due to AD, and 9 MCI patients who had an amyloid-negative scan were included. Regions of interest were defined on co-registered MRI, and the PIB standardized uptake value ratio (SUVR) on the same regions was used over follow-up. Annual change in PIB SUVR was calculated. Patients with MCI due to AD had higher baseline PIB SUVR (1.81±0.32, n = 39, p < 0.01) and a greater annual rate of change in PIB SUVR (0.044±0.027, n = 39, p < 0.01) compared to amyloid-negative MCI patients. Twenty-eight (71.8%) progressed to AD. In patients who progressed during a short duration of 1.7±0.8 years, the annual rate of increase in PIB SUVR was 0.101±0.094 (n = 16, p < 0.05), which was greater compared to patients with long conversion or stable patients. There was a negative correlation between the annual rate of increase in PIB SUVR and duration of progression to AD among individual MCI converters (r = -0.47, n = 28, p < 0.05). The patients defined as MCI due to AD could progress to AD with a shorter period if they have a greater increased annual rate in brain Aβ deposition.

%B J Alzheimers Dis %V 57 %P 765-773 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304292?dopt=Abstract %R 10.3233/JAD-161074 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Efficacy of Emotion Recognition Rehabilitation for People with Alzheimer's Disease. %A García-Casal, J Antonio %A Goñi-Imizcoz, Miguel %A Perea-Bartolomé, M Victoria %A Soto-Pérez, Felipe %A Smith, Sarah Jane %A Calvo-Simal, Sara %A Franco-Martín, Manuel %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Therapy %K Depression %K Emotions %K Female %K Follow-Up Studies %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Outcome Assessment (Health Care) %K Recognition (Psychology) %K Single-Blind Method %K Statistics, Nonparametric %X

BACKGROUND: The ability to recognize emotional expression is essential for social interactions, adapting to the environment, and quality of life. Emotion recognition is impaired in people with Alzheimer's disease (AD), thus rehabilitation of these skills has the potential to elicit significant benefits.

OBJECTIVE: This study sought to establish whether emotion recognition capacity could be rehabilitated in people with AD.

METHODS: Thirty-six participants with AD were assigned to one of three conditions: an experimental group (EG) that received 20 sessions of rehabilitation of emotion recognition and 20 sessions of cognitive stimulation therapy (CST), a control group (CG) that received 40 sessions of CST, and a treatment as usual group (TAU).

RESULTS: A positive treatment effect favoring the EG was found; participants were better able to correctly identify emotions (p = 0.021), made fewer errors of commission (p = 0.002), had greater precision of processing (p = 0.021), and faster processing speed (p = 0.001). Specifically, the EG were better able to identify sadness (p = 0.016), disgust (p = 0.005), and the neutral expression (p = 0.014), with quicker processing speed for disgust (p = 0.002). These gains were maintained at one month follow-up with the exception of processing speed for surprise, which improved.

CONCLUSION: Capacity to recognize facial expressions of emotions can be improved through specific rehabilitation in people with AD, and gains are still present at a one month follow up. These findings have implications for the design of rehabilitation techniques for people with AD that may lead to improved quality of life and social interactions for this population.

%B J Alzheimers Dis %V 57 %P 937-951 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304290?dopt=Abstract %R 10.3233/JAD-160940 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort. %A Kramberger, Milica G %A Auestad, Bjørn %A Garcia-Ptacek, Sara %A Abdelnour, Carla %A Olmo, Josep Garre %A Walker, Zuzana %A Lemstra, Afina W %A Londos, Elisabet %A Blanc, Frédéric %A Bonanni, Laura %A McKeith, Ian %A Winblad, Bengt %A de Jong, Frank Jan %A Nobili, Flavio %A Stefanova, Elka %A Petrova, Maria %A Falup-Pecurariu, Cristian %A Rektorova, Irena %A Bostantjopoulou, Sevasti %A Biundo, Roberta %A Weintraub, Daniel %A Aarsland, Dag %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognition Disorders %K Cohort Studies %K Female %K Humans %K International Cooperation %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %X

BACKGROUND/OBJECTIVE: The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) patients.

METHODS: Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features.

RESULTS: The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p = 0.07 compared to DLB) and 1.8 in PDD (p = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features.

CONCLUSIONS: The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

%B J Alzheimers Dis %V 57 %P 787-795 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304294?dopt=Abstract %R 10.3233/JAD-161109 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Frontotemporal Dementia GWAS Loci with Late-Onset Alzheimer's Disease in a Northern Han Chinese Population. %A Tan, Chen-Chen %A Wan, Yu %A Tan, Meng-Shan %A Zhang, Wei %A Wang, Zi-Xuan %A Sun, Fu-Rong %A Miao, Dan %A Tan, Lan %A Yu, Jin-Tai %K Age of Onset %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Asian Continental Ancestry Group %K Case-Control Studies %K China %K Female %K Frontotemporal Dementia %K Gene Frequency %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Genotyping Techniques %K Humans %K Linkage Disequilibrium %K Male %K Mental Status Schedule %K Polymorphism, Single Nucleotide %X

BACKGROUND: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are a class of neurodegenerative diseases. Strong similarities in cerebrospinal fluid biomarker, imaging markers, and disease progression profiles suggest that some or most of the pathophysiology is shared between AD and FTD. A recent large genome-wide association study reported several single nucleotide polymorphisms (SNPs) at the RAB38, RAB38/CTSC, HLA-DRA/HLA-DRB5, and BTNL2 in association with FTD.

OBJECTIVE: To explore whether these SNPs are associated with AD risk.

METHODS: We conducted a case-control study to investigate the association of FTD-associated loci in 2338 Han Chinese subjects.

RESULTS: We observed significant differences in genotype distributions of rs302668 (pc = 0.025), rs9268877 (pc = 0.025), rs9268856 (p <  0.001), and rs1980493 (pc = 0.045) between cases and controls. The SNPs rs16913634 for RAB38/CTSC was unrelated to LOAD risk (p = 0.088).

CONCLUSION: The SNPs rs302668 in RAB38, rs9268877 and rs9268856 polymorphism in HLA-DRA/HLA-DRB5, and rs1980493 polymorphism in BTNL2 might play a role in the susceptibility to late-onset AD in the Han Chinese population.

%B J Alzheimers Dis %V 52 %P 43-50 %8 2016 02 26 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967218?dopt=Abstract %R 10.3233/JAD-151073 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Associations between Neuropsychiatric Symptoms and Cerebral Amyloid Deposition in Cognitively Impaired Elderly People. %A Bensamoun, David %A Guignard, Renaud %A Furst, Ansgar J %A Derreumaux, Alexandre %A Manera, Valeria %A Darcourt, Jacques %A Benoit, Michel %A Robert, Philippe H %A David, Renaud %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloidogenic Proteins %K Cerebral Cortex %K Cognition Disorders %K Cohort Studies %K Female %K Fluorodeoxyglucose F18 %K Humans %K Male %K Mental Status Schedule %K Mood Disorders %K Neuropsychological Tests %K Positron-Emission Tomography %X

BACKGROUND: Neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect the majority of patients with dementia, and result in a greater cognitive and functional impairment.

OBJECTIVE: To investigate associations between BPSD and amyloid cerebral deposition as measured by 18F-Florbetapir-PET quantitative uptake in elderly subjects with and without cognitive impairment.

METHODS: Participants with cognitive impairment [mild cognitive impairment (MCI) or Alzheimer's disease (AD)] and healthy controls (HC) from the ADNI cohort (Alzheimer Disease Neuroimaging Initiative) who underwent an 18F-florbetapir PET scan between May 2010 and March 2014 were included. Clinical assessments included the Clinical Dementia Rating, the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Freesurfer software was used to extract PET counts based on T1-based structural ROI (frontal, cingulate, parietal, and temporal). Spearman's partial correlation scores between BPSD severity and regional amyloid uptake were calculated.

RESULTS: Data for 657 participants [age = 72.6 (7.19); MMSE = 27.4 (2.67)] were analyzed, including 230 HC [age = 73.1 (6.02); MMSE = 29 (1.21)], 308 MCI [age = 71.5 (7.44); MMSE = 28.0 (1.75)], and 119 AD subjects [age = 74.7 (8.05); MMSE = 23.1 (2.08)]. Considering all diagnostic groups together, positive significant correlations were found between anxiety and 18F-florbetapir uptake in the frontal (r = 0.102; p = 0.009), cingulate (r = 0.083; p = 0.034), and global cerebral uptake (r = 0.099; p = 0.011); between irritability and frontal (r = 0.089; p = 0.023), cingulate (r = 0.085; p = 0.030), parietal (r = 0.087; p = 0.025), and global cerebral uptake (r = 0.093; p = 0.017); in the MCI subgroup, between anxiety and frontal (r = 0.126; p = 0.03) and global uptake (r = 0.14; p = 0.013); in the AD subgroup, between irritability and parietal uptake (r = 0.201; p = 0.03).

CONCLUSION: Anxiety and irritability are associated with greater amyloid deposition in the neurodegenerative process leading to AD.

%B J Alzheimers Dis %V 49 %P 387-98 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484900?dopt=Abstract %R 10.3233/JAD-150181 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Associations between Serum Omega-3 Fatty Acid Levels and Cognitive Functions among Community-Dwelling Octogenarians in Okinawa, Japan: The KOCOA Study. %A Nishihira, Junko %A Tokashiki, Takashi %A Higashiuesato, Yasushi %A Willcox, Donald Craig %A Mattek, Nora %A Shinto, Lynne %A Ohya, Yusuke %A Dodge, Hiroko H %K Age Factors %K Aged, 80 and over %K Arachidonic Acid %K Blood Chemical Analysis %K Cognition %K Cross-Sectional Studies %K Educational Status %K Fatty Acids, Omega-3 %K Female %K Humans %K Japan %K Logistic Models %K Male %K Mental Status Schedule %K Obesity %K Prospective Studies %K Sex Factors %X

BACKGROUND: Epidemiological studies have found frequent consumption of fatty fish is protective against cognitive decline. However, the association between circulating omega-3 polyunsaturated fatty acid (PUFA) levels and cognitive functions among the oldest old is not well known.

OBJECTIVE: To examine the association between serum PUFA levels and cognitive function among community-dwelling, non-demented elderly aged over 80 years old.

METHODS: The data came from the Keys to Optimal Cognitive Aging (KOCOA) study; an ongoing cohort of relatively healthy volunteers aged over 80 years old, living in Okinawa, Japan. One hundred eighty five participants (mean age 84.1±3.4 years) assessed in 2011 who were free from frank dementia (defined as Clinical Dementia Rating <1.0) were used for the current cross-sectional study. We examined whether serum omega-3 PUFAs (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), arachidonic acid (AA), EPA/AA ratio, DHA/AA ratio, and DHA+EPA are associated with (1) age and (2) global cognitive function (Japanese MMSE) and executive function (Verbal Fluency Letter). Data was analyzed univariately by t-test and multivariately by cumulative logistic regression models controlling for age, gender, years of education, obesity, hypertension, diabetes, and dyslipidemia.

RESULTS: Serum DHA levels decreased with increasing age (p = 0.04). Higher global cognitive function was associated with higher levels of serum EPA (p = 0.03) and DHA + EPA (p = 0.03) after controlling for confounders.

CONCLUSIONS: Higher serum EPA and DHA + EPA levels were independently associated with better scores on global cognitive function among the oldest old, free from dementia. Longitudinal follow-up studies are warranted.

%B J Alzheimers Dis %V 51 %P 857-66 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890763?dopt=Abstract %R 10.3233/JAD-150910 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer's Disease Biomarkers. %A Malishkevich, Anna %A Marshall, Gad A %A Schultz, Aaron P %A Sperling, Reisa A %A Aharon-Peretz, Judith %A Gozes, Illana %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Chi-Square Distribution %K Cognitive Dysfunction %K Cohort Studies %K Female %K Homeodomain Proteins %K Humans %K Independent Living %K Intelligence %K Male %K Mental Status Schedule %K Middle Aged %K Nerve Tissue Proteins %K Peptide Fragments %K RNA, Messenger %K tau Proteins %X

Biomarkers for Alzheimer's disease (AD) are vital for disease detection in the clinical setting. Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) is essential for brain formation and linked to cognitive functions. Here, we revealed that blood borne expression of ADNP and its paralog ADNP2 is correlated with premorbid intelligence, AD pathology, and clinical stage. Age adjustment showed significant associations between: 1) higher premorbid intelligence and greater serum ADNP, and 2) greater cortical amyloid and lower ADNP and ADNP2 mRNAs. Significant increases in ADNP mRNA levels were observed in patients ranging from mild cognitive impairment (MCI) to AD dementia. ADNP2 transcripts showed high correlation with ADNP transcripts, especially in AD dementia lymphocytes. ADNP plasma/serum and lymphocyte mRNA levels discriminated well between cognitively normal elderly, MCI, and AD dementia participants. Measuring ADNP blood-borne levels could bring us a step closer to effectively screening and tracking AD.

%B J Alzheimers Dis %V 50 %P 249-60 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639975?dopt=Abstract %R 10.3233/JAD-150799 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Characteristics of Alzheimer's Disease Patients with Severe Executive Disorders. %A Godefroy, Olivier %A Bakchine, Serge %A Verny, Marc %A Delabrousse-Mayoux, Jean-Philippe %A Roussel, Martine %A Pere, Jean-Jacques %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Caregivers %K Cost of Illness %K Executive Function %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prevalence %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Executive dysfunctions in Alzheimer's disease (AD) have been assessed using variable batteries and/or in selected populations.

OBJECTIVE: The primary objective of this observational study was to determine the prevalence and severity of executive dysfunction in AD patients using a previously validated battery. The secondary objective was to determine the characteristics including treatment outcomes of AD patients with severe executive dysfunction.

METHODS: The study included AD patients with mild-to-moderate dementia aged 60 or over, consulting in various clinical settings including memory clinics and requiring the introduction of an antidementia drug. Executive dysfunction was examined using a validated, shortened executive battery.

RESULTS: 381 patients were included. Executive dysfunctions were observed in 88.2% of the patients (95% CI: 84.9-91.4) and were severe (defined as ≥2/3 impaired scores) in 80.4% (95% CI: 76.9-84.8). Global hypoactivity with apathy was more frequent (p = 0.0001) than impairment in executive function tests. The 308 patients with severe executive dysfunction were older (p = 0.003) and had more severe dementia (p = 0.0001). Similarly, in the subset of 257 patients with mild dementia, individuals with severe executive dysfunction were older (p = 0.003) and had more severe dementia. Global hypoactivity was independently associated with difficulties in IADL and a higher caregiver burden (p = 0.0001 for both). The severity of executive dysfunction did not significantly influence the patients' outcomes at 6 months.

CONCLUSIONS: Executive dysfunction is a very common disorder in a representative population of patients with mild-to-moderate AD. It was independently correlated with impaired autonomy and increased caregiver burden but did not significantly influence treatment outcomes.

%B J Alzheimers Dis %V 51 %P 815-25 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890770?dopt=Abstract %R 10.3233/JAD-150971 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Cognitive Change Index as a Measure of Self and Informant Perception of Cognitive Decline: Relation to Neuropsychological Tests. %A Rattanabannakit, Chatchawan %A Risacher, Shannon L %A Gao, Sujuan %A Lane, Kathleen A %A Brown, Steven A %A McDonald, Brenna C %A Unverzagt, Frederick W %A Apostolova, Liana G %A Saykin, Andrew J %A Farlow, Martin R %K Adult %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognitive Dysfunction %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Perception %K Self Report %X

BACKGROUND: The perception of cognitive decline by individuals and those who know them well ("informants") has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms.

OBJECTIVE: We investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms.

METHODS: 267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models.

RESULTS: CCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant.

CONCLUSION: Self- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome.

%B J Alzheimers Dis %V 51 %P 1145-55 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923008?dopt=Abstract %R 10.3233/JAD-150729 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Stimulation Modulates Platelet Total Phospholipases A2 Activity in Subjects with Mild Cognitive Impairment. %A Balietti, Marta %A Giuli, Cinzia %A Fattoretti, Patrizia %A Fabbietti, Paolo %A Postacchini, Demetrio %A Conti, Fiorenzo %K Blood Platelets %K Cognition %K Cognitive Dysfunction %K Cognitive Therapy %K Cohort Studies %K Humans %K Mental Status Schedule %K Neuropsychological Tests %K Phospholipases A2 %K Treatment Outcome %X

We evaluated the effect of cognitive stimulation (CS) on platelet total phospholipases A2 activity (tPLA2A) in patients with mild cognitive impairment (MCI_P). At baseline, tPLA2A negatively correlated with Mini-Mental State Examination score (MMSE_s): patients with MMSE_s <26 (Subgroup 1) had significantly higher activity than those with MMSE_s ≥26 (Subgroup 2), who had values similar to the healthy elderly. Regarding CS effect, Subgroup 1 had a significant tPLA2A reduction, whereas Subgroup 2 did not significantly changes after training. Our results showed for the first time that tPLA2A correlates with the cognitive conditions of MCI_P, and that CS acts selectively on subjects with a dysregulated tPLA2A.

%B J Alzheimers Dis %V 50 %P 957-62 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836161?dopt=Abstract %R 10.3233/JAD-150714 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comparing the Effects of Multisensory Stimulation and Individualized Music Sessions on Elderly People with Severe Dementia: A Randomized Controlled Trial. %A Sánchez, Alba %A Maseda, Ana %A Marante-Moar, M Pilar %A de Labra, Carmen %A Lorenzo-López, Laura %A Millán-Calenti, José Carlos %K Affect %K Aged %K Aged, 80 and over %K Anxiety %K Cognition %K Dementia %K Environment %K Female %K Follow-Up Studies %K Humans %K Male %K Mental Status Schedule %K Music Therapy %K Precision Medicine %K Sensory Art Therapies %K Severity of Illness Index %K Treatment Outcome %X

The objective of this study was to compare the effects of a multisensory stimulation environment (MSSE) and individualized music sessions on agitation, emotional and cognitive status, and dementia severity in a sample of institutionalized patients with severe dementia. Twenty-two participants with a diagnosis of severe or very severe dementia were randomly assigned to two groups: MSSE and individualized music sessions. Both groups participated in two 30-min weekly sessions over 16 weeks. Outcomes were agitation (Cohen-Mansfield Agitation Inventory, CMAI), mood (Cornell Scale for Depression in Dementia, CSDD), anxiety (Rating Anxiety in Dementia, RAID), cognitive function (Severe Mini-Mental State Examination, SMMSE), and the overall severity of dementia (Bedford Alzheimer Nursing Severity Scale, BANS-S). They were assessed at baseline (pre-trial), in the middle (mid-trial), at the end of the intervention (post-trial), and 8 weeks after the intervention (follow-up). Patients in the MSSE group showed significant improvement in their RAID and BANS-S scores compared with the individualized music group post- versus pre-trial. With regard to agitation, there was improvement during the intervention in both the MSSE and individualized music groups in the CMAI total score after 16 weeks of intervention, with no significant differences between the groups. The results suggest that MSSE could have better effects on anxiety symptoms and dementia severity in comparison with individualized music sessions in elderly patients with severe dementia.

%B J Alzheimers Dis %V 52 %P 303-15 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060958?dopt=Abstract %R 10.3233/JAD-151150 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Course and Determinants of Anosognosia in Alzheimer's Disease: A 12-Month Follow-up. %A Turró-Garriga, Oriol %A Garre-Olmo, Josep %A Calvó-Perxas, Laia %A Reñé-Ramírez, Ramón %A Gascón-Bayarri, Jordi %A Conde-Sala, Josep Lluís %K Age Factors %K Aged %K Agnosia %K Alzheimer Disease %K Disability Evaluation %K Disease Progression %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Incidence %K Logistic Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prevalence %K Prospective Studies %K Risk Factors %K Severity of Illness Index %X

Anosognosia in Alzheimer's disease (AD) has been associated with greater cognitive impairment and more behavioural and psychological symptoms of dementia (BPSD). This study examines the incidence, persistence, and remission rates of anosognosia over a 12-month period, as well as the related risk factors. This was an observational 12-month prospective study. The longitudinal sample comprised 177 patients with mild or moderate AD, and their respective caregivers. Anosognosia was assessed using the Anosognosia Questionnaire in Dementia, and we also evaluated cognitive status (Mini-Mental State Examination), functional disability (Disability Assessment in Dementia), and the presence of BPSD (Neuropsychiatric Inventory). Multinomial logistic regression was used to determine the variables associated with the incidence, persistence and remission of anosognosia. The prevalence of anosognosia was 39.5% (95% CI = 32.1-47.1) at baseline. At 12 months, incidence was 38.3% (95% CI = 28.6-48.0), persistence was 80.0% (95% CI = 69.9-90.1) and remission was 20.0% (95% CI = 9.9-30.1). The regression model identified lower age, more education, and the presence of delusions as variables associated with incidence, and more education, lower instrumental DAD score, and disinhibition as variables associated with persistence. No variables were associated with remission (n = 14). The presence of anosognosia in AD patients is high. Education and certain neuropsychiatric symptoms may explain a greater and earlier incidence of anosognosia. However, anosognosia also increases with greater cognitive impairment and disease severity.

%B J Alzheimers Dis %V 51 %P 357-66 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890611?dopt=Abstract %R 10.3233/JAD-150706 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia. %A Vallortigara, Julie %A Whitfield, David %A Quelch, William %A Alghamdi, Amani %A Howlett, David %A Hortobágyi, Tibor %A Johnson, Mary %A Attems, Johannes %A O'Brien, John T %A Thomas, Alan %A Ballard, Clive G %A Aarsland, Dag %A Francis, Paul T %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Amyloid beta-Peptides %K Analysis of Variance %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Regression Analysis %K Synaptophysin %K tau Proteins %K Vesicle-Associated Membrane Protein 2 %X

Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p <  0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

%B J Alzheimers Dis %V 50 %P 101-10 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639969?dopt=Abstract %R 10.3233/JAD-150707 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Delusions in Patients with Alzheimer's Disease: A Multidimensional Approach. %A D'Onofrio, Grazia %A Panza, Francesco %A Sancarlo, Daniele %A Paris, Francesco F %A Cascavilla, Leandro %A Mangiacotti, Antonio %A Lauriola, Michele %A Paroni, Giulia H %A Seripa, Davide %A Greco, Antonio %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Delusions %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prognosis %K Risk %K Severity of Illness Index %K Time Factors %X

In Alzheimer's disease (AD) patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. We determined the effect of delusions on mortality risk, clinical outcomes linked to comprehensive geriatric assessment (CGA), cognitive, depressive, and neuropsychiatric symptoms (NPS) in 380 consecutive AD patients with Mini-Mental State Examination, Clinical Dementia Rating scale, 15-item Geriatric Depression Scale, and Neuropsychiatric Inventory (NPI), assessing one-year mortality risk using the Multidimensional Prognostic Index (MPI). We included 121 AD patients with delusions (AD-D) and 259 AD patients without delusions (AD-noD). AD-D patients were significantly older, with higher age at onset and cognitive impairment, a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant. At CGA, AD-D patients showed a higher grade of disability in basic and instrumental activities of daily living, and an increased risk of malnutrition and bedsores. The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p <  0.0001) and MPI grade. AD-D patients showed also a significant higher score in NPI of the following NPS than AD-noD patients: hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Therefore, AD-D patients showed higher dementia severity, and higher impairment in cognitive and depressive symptoms, and several neuropsychiatric domains than AD-noD patients, and this appeared to be associated with higher multidimensional impairment and increased risk of mortality.

%B J Alzheimers Dis %V 51 %P 427-37 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890768?dopt=Abstract %R 10.3233/JAD-150944 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dementia Apraxia Test (DATE): A Brief Tool to Differentiate Behavioral Variant Frontotemporal Dementia from Alzheimer's Dementia Based on Apraxia Profiles. %A Johnen, Andreas %A Frommeyer, Jana %A Modes, Fenja %A Wiendl, Heinz %A Duning, Thomas %A Lohmann, Hubertus %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Apraxias %K Diagnosis, Differential %K Female %K Frontotemporal Dementia %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Psychometrics %K Reference Values %X

BACKGROUND: Standardized praxis assessments with modern, empirically validated screening tests have substantially improved clinical evaluation of apraxia in patients with stroke. Although apraxia may contribute to early differential diagnosis of Alzheimer's dementia (AD) and behavioral variant frontotemporal dementia (bvFTD), no comparable test is readily available to clinicians for this purpose to date.

OBJECTIVE: To design a clinically useful apraxia test for the differentiation of AD and bvFTD.

METHODS: 84 test items pertaining to twelve praxis subdomains were evaluated for their efficacy to discriminate between patients with bvFTD (n = 24), AD (n = 28), and elderly healthy controls (HC; n = 35). Items were then selected based on discriminative value and psychometric properties.

RESULTS: Items indicative of mild AD comprised spatially complex imitation of hand and finger postures and to a lesser degree, pantomime of common object-use. Buccofacial apraxia including imitation of face postures, emblematic face postures, and repetition of multisyllabic pseudowords differentiated bvFTD from HC and AD. The final test version consisting of 20 items proved highly efficient for the discrimination of biologically confirmed dementia patients from HC (sensitivity 91% , specificity 71%) but also for differential diagnosis of bvFTD and AD (sensitivity 74% , specificity 93%).

CONCLUSIONS: Assessment of praxis profiles effectively contributes to diagnosis and differential diagnosis of AD and bvFTD. The Dementia Apraxia Test (DATE) is a brief and easy to administer cognitive tool for dementia assessment, has a high inter-rater reliability (Cohen's κ= 0.885) and demonstrates content validity.

%B J Alzheimers Dis %V 49 %P 593-605 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484911?dopt=Abstract %R 10.3233/JAD-150447 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Diagnosis of Dementia with High Levels of Cerebrospinal Fluid Tau Protein. %A Grangeon, Lou %A Paquet, Claire %A Bombois, Stephanie %A Quillard-Muraine, Muriel %A Martinaud, Olivier %A Bourre, Bertrand %A Lefaucheur, Romain %A Nicolas, Gaël %A Dumurgier, Julien %A Gerardin, Emmanuel %A Jan, Mary %A Laplanche, Jean-Louis %A Peoc'h, Katell %A Hugon, Jacques %A Pasquier, Florence %A Maltête, David %A Hannequin, Didier %A Wallon, David %K Adult %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Creutzfeldt-Jakob Syndrome %K Dementia, Vascular %K Diagnosis, Differential %K Female %K France %K Frontotemporal Dementia %K Humans %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %K Phosphorylation %K Retrospective Studies %K Sex Factors %K tau Proteins %X

BACKGROUND: Total Tau concentration in cerebrospinal fluid (CSF) is widely used as a biomarker in the diagnosis of neurodegenerative process primarily in Alzheimer's disease (AD). A particularly high Tau level may indicate AD but may also be associated with Creutzfeldt-Jakob disease (CJD). In such situations little is known about the distribution of differential diagnoses.

OBJECTIVE: Our study aimed to describe the different diagnoses encountered in clinical practice for patients with dementia and CSF Tau levels over 1000 pg/ml. We studied the p-Tau/Tau ratio to specify its ability to distinguish AD from CJD.

METHODS: Patients (n = 202) with CSF Tau levels over 1000 pg/ml were recruited in three memory clinics in France. All diagnoses were made using the same diagnostic procedure and criteria.

RESULTS: Patients were diagnosed with AD (n = 148, 73.2%), mixed dementia (n = 38, 18.8%), CJD, vascular dementia (n = 4, 2.0% for each), Lewy body dementia, and frontotemporal dementia (n = 3, 1.5% for each). Dispersion of CSF Tau levels clearly showed an overlap between all diagnoses. Using the p-Tau/Tau ratio suggestive of CJD (<0.075), all CJD patients were correctly categorized and only two AD patients were miscategorized. This ratio was highly associated with CJD compared to AD (p < 0.0001).

CONCLUSION: Our study showed that in clinical practice, extremely high CSF Tau levels are mainly related to diagnosis of AD. CJD patients represent a minority. Our results support a sequential interpretation algorithm for CSF biomarkers in dementia. High CSF Tau levels should alert clinicians to check the p-Tau/Tau ratio to consider a probable diagnosis of CJD.

%B J Alzheimers Dis %V 51 %P 905-13 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890785?dopt=Abstract %R 10.3233/JAD-151111 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Mass Spectrometry Profiles of Tau Protein in the Cerebrospinal Fluid of Patients with Alzheimer's Disease, Progressive Supranuclear Palsy, and Dementia with Lewy Bodies. %A Barthélemy, Nicolas R %A Gabelle, Audrey %A Hirtz, Christophe %A Fenaille, François %A Sergeant, Nicolas %A Schraen-Maschke, Susanna %A Vialaret, Jérôme %A Buée, Luc %A Junot, Christophe %A Becher, François %A Lehmann, Sylvain %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Analysis of Variance %K Chromatography, Liquid %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Peptide Fragments %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %K Statistics as Topic %K Supranuclear Palsy, Progressive %K tau Proteins %X

Microtubule-associated Tau proteins are major actors in neurological disorders, the so-called tauopathies. In some of them, and specifically in Alzheimer's disease (AD), hyperphosphorylated forms of Tau aggregate into neurofibrillary tangles. Following and understanding the complexity of Tau's molecular profile with its multiple isoforms and post-translational modifications represent an important issue, and a major analytical challenge. Immunodetection methods are, in fact, limited by the number, specificity, sensitivity, and capturing property of the available antibodies. Mass spectrometry (MS) has recently allowed protein quantification in complex biological fluids using isotope-labeled recombinant standard for absolute quantification (PSAQ). To study Tau proteins, which are found at very low concentrations within the cerebrospinal fluid (CSF), we relied on an innovative two-step pre-fractionation strategy, which was not dependent on immuno-enrichment. We then developed a sensitive multiplex peptide detection capability using targeted high-resolution MS to quantify Tau-specific peptides covering its entire sequence. This approach was used on a clinical cohort of patients with AD, progressive supranuclear palsy (PSP), and dementia with Lewy body (DLB) and with control non-neurodegenerative disorders. We uncovered a common CSF Tau molecular profile characterized by a predominance of central core expression and 1N/3R isoform detection. While PSP and DLB tau profiles showed minimal changes, AD was characterized by a unique pattern with specific modifications of peptide distribution. Taken together these results provide important information on Tau biology for future therapeutic interventions, and improved molecular diagnosis of tauopathies.

%B J Alzheimers Dis %V 51 %P 1033-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923020?dopt=Abstract %R 10.3233/JAD-150962 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Disconnection Hypothesis in Alzheimer's Disease Studied Through Multimodal Magnetic Resonance Imaging: Structural, Perfusion, and Diffusion Tensor Imaging. %A Lacalle-Aurioles, María %A Navas-Sánchez, Francisco Javier %A Alemán-Gómez, Yasser %A Olazarán, Javier %A Guzmán-De-Villoria, Juan Adán %A Cruz-Orduña, Isabel %A Mateos-Pérez, José María %A Desco, Manuel %K Aged %K Alzheimer Disease %K Brain %K Brain Mapping %K Cerebral Angiography %K Cerebrovascular Circulation %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Female %K Functional Laterality %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Models, Neurological %K Multimodal Imaging %K Organ Size %K Prospective Studies %X

According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer's disease (AD) may lead to reduced activity of target neurons in cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r = 0.90, p <  0.0001; right: r = 0.597, p = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r = 0.551, p = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group.

%B J Alzheimers Dis %V 50 %P 1051-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890735?dopt=Abstract %R 10.3233/JAD-150288 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Distinct Patterns of Cognitive Aging Modified by Education Level and Gender among Adults with Limited or No Formal Education: A Normative Study of the Mini-Mental State Examination. %A Xie, Haiqun %A Zhang, Chengguo %A Wang, Yukai %A Huang, Shuyun %A Cui, Wei %A Yang, Wenbin %A Koski, Lisa %A Xu, Xiping %A Li, Youbao %A Zheng, Meili %A He, Mingli %A Fu, Jia %A Shi, Xiuli %A Wang, Kai %A Tang, Genfu %A Wang, Binyan %A Huo, Yong %K Adult %K Aged %K Aged, 80 and over %K China %K Cognition Disorders %K Cognitive Aging %K Educational Status %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Reference Values %K Rural Population %K Sex Characteristics %X

BACKGROUND: Dementia is increasingly prevalent due to rapid aging of the population, but under-recognized among people with low education levels. This is partly due to a lack of appropriate and precise normative data, which underestimates cognitive aging in the use of screening tools for dementia.

OBJECTIVE: We aimed to improve the precision of screening for cognitive impairment, by characterizing the patterns of cognitive aging and derived normative data of the Mini-Mental State Examination (MMSE) for illiterate and low-educated populations.

METHODS: This community-based study included data from 2,280 individuals aged 40 years or older from two rural areas. Multiple linear modeling examined the effect of aging on cognition reflected by the MMSE, stratified by education level and gender. Threshold effect of age on cognition was performed using a smoothing function.

RESULTS: The majority of participants (60.4%) were illiterate or had attended only primary school (24.6%). The effect of aging on cognition varied by gender and education. Primary-school educated females and males remained cognitively stable up to 62 and 71 years of age, respectively, with MMSE score declining 0.4 and 0.8 points/year in females and males thereafter. Illiterates females scored 2.3 points lower than illiterate males, and scores for both declined 0.2 points/year. According to these results, normative data stratified by age, education and gender was generated.

CONCLUSION: This study suggests gender and educational differences exist in cognitive aging among adults with limited or no formal education. To improve screening precision for cognitive impairment with the use of MMSE in low-educated population, age, gender, and education level should be considered.

%B J Alzheimers Dis %V 49 %P 961-9 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756324?dopt=Abstract %R 10.3233/JAD-143066 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil Standard Dose in Japanese Patients with Severe Alzheimer's Disease: A Randomized, Double-Blind Trial. %A Homma, Akira %A Atarashi, Hirotsugu %A Kubota, Naoki %A Nakai, Kenya %A Takase, Takao %K Aged %K Alzheimer Disease %K Cholinesterase Inhibitors %K Delayed-Action Preparations %K Double-Blind Method %K Female %K Humans %K Indans %K Japan %K Male %K Mental Status Schedule %K Nootropic Agents %K Outpatients %K Piperidines %K Psychiatric Status Rating Scales %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Donepezil is an established treatment for mild, moderate, and severe Alzheimer's disease (AD). An international study demonstrated superior efficacy of sustained release (SR) 23 mg/day donepezil over immediate release (IR) 10 mg/day donepezil for cognitive function, but not global function in moderate-to-severe AD.

OBJECTIVE: To demonstrate the superiority of SR 23 mg/day donepezil over IR 10 mg/day donepezil in Japanese patients with severe AD (SAD).

METHODS: In this multicenter, randomized, double-blind, parallel-group study, Japanese outpatients with SAD were randomly assigned to continue IR 10 mg/day or switch to SR 23 mg/day for 24 weeks. Endpoints included the Severe Impairment Battery (SIB), Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus), and safety.

RESULTS: Overall, 166 and 185 patients were randomized to receive IR 10 mg/day and SR 23 mg/day, respectively. SR 23 mg/day was not statistically superior to IR 10 mg/day by SIB (least squares mean difference [LSMD]: 0.0; 95% confidence interval [CI]: -1.7, 1.8; p = 0.981) or CIBIC-plus (LSMD: 0.2; 95% CI: 0.0, 0.4; p = 0.080). Common adverse events in the SR 23 mg group were decreased appetite, vomiting, diarrhea, and contusion. Safety findings were consistent with known safety profiles of donepezil.

CONCLUSION: SR 23 mg/day donepezil was not superior to IR 10 mg/day donepezil regarding the efficacy endpoints for Japanese SAD. Considering that a 10 mg/day dose is approved for SAD in Japan, the present findings suggest that IR 10 mg/day donepezil is the optimal dosage for Japanese patients with SAD.

%B J Alzheimers Dis %V 52 %P 345-57 %8 2016 03 11 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967222?dopt=Abstract %R 10.3233/JAD-151149 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Exercise Plus Cognitive Performance Over and Above Exercise Alone in Subjects with Mild Cognitive Impairment. %A Sacco, Guillaume %A Caillaud, Corinne %A Ben Sadoun, Gregory %A Robert, Philippe %A David, Renaud %A Brisswalter, Jeanick %K Aged %K Analysis of Variance %K Cognitive Dysfunction %K Cognitive Therapy %K Exercise %K Exercise Therapy %K Female %K Humans %K Inhibition (Psychology) %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Reaction Time %K Retrospective Studies %K Treatment Outcome %X

BACKGROUND: Epidemiological studies highlight the relevance of regular exercise interventions to enhance or maintain neurocognitive function in subjects with cognitive impairments.

OBJECTIVES: The aim of this study was to ascertain the effect of aerobic exercise associated with cognitive enrichment on cognitive performance in subjects with mild cognitive impairment (MCI).

METHOD: Eight participants with MCI (72 ± 2 years) were enrolled in a 9-month study that consisted of two 3-months experimental interventions separated by a training cessation period of 3 months. The interventions included either aerobic exercise alone or aerobic exercise combined with cognitive enrichment. The exercise program involved two 20-min cycling exercise bouts per week at an intensity corresponding to 60% of the heart rate reserve. Cognitive performance was assessed using a task of single reaction time (SRT) and an inhibition task (Go-no-Go) before, immediately after, and 1 month after each intervention.

RESULTS: The exercise intervention improved the speed of responses during the Go-no-Go task without any increase in errors. This improvement was enhanced by cognitive enrichment (6 ± 1% ; p >  0.05), when compared with exercise alone (4 ± 0.5% ,). Following exercise cessation, this positive effect disappeared. No effect was observed on SRT performance.

CONCLUSION: Regular aerobic exercise improved cognitive performance in MCI subjects and the addition of cognitive tasks during exercise potentiated this effect. However, the influence of aerobic exercise on cognitive performance did not persist after cessation of training. Studies involving a larger number of subjects are necessary to confirm these results.

%B J Alzheimers Dis %V 50 %P 19-25 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639954?dopt=Abstract %R 10.3233/JAD-150194 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Functional Connectivity of Ventral and Dorsal Visual Streams in Posterior Cortical Atrophy. %A Migliaccio, Raffaella %A Gallea, Cécile %A Kas, Aurélie %A Perlbarg, Vincent %A Samri, Dalila %A Trotta, Laura %A Michon, Agnès %A Lacomblez, Lucette %A Dubois, Bruno %A Lehéricy, Stéphane %A Bartolomeo, Paolo %K Aged %K Alzheimer Disease %K Atrophy %K Case-Control Studies %K Cerebral Cortex %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Oxygen %K Visual Pathways %X

BACKGROUND: Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC).

OBJECTIVES: To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer's disease (AD) pathology.

METHODS: Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy.

RESULTS: PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls.

CONCLUSIONS: FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.

%B J Alzheimers Dis %V 51 %P 1119-30 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923019?dopt=Abstract %R 10.3233/JAD-150934 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Genetic Variability of UCP4 Affects the Individual Susceptibility to Late-Onset Alzheimer's Disease and Modifies the Disease's Risk in APOE-ɛ4 Carriers. %A Montesanto, Alberto %A Crocco, Paolina %A Anfossi, Maria %A Smirne, Nicoletta %A Puccio, Gianfranco %A Colao, Rosanna %A Maletta, Raffaele %A Passarino, Giuseppe %A Bruni, Amalia C %A Rose, Giuseppina %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Female %K Genetic Association Studies %K Genotype %K Humans %K Male %K Mental Status Schedule %K Mitochondrial Uncoupling Proteins %K Neuroimaging %K Polymorphism, Single Nucleotide %X

Uncoupling proteins (UCPs) are a group of five mitochondrial inner membrane transporters with a tissue specific expression that uncouple biofuel oxidation from ATP synthesis and function as regulators of energy homeostasis and antioxidants. Previous data suggested that neuronal UCPs (UCP2, UCP4, and UCP5) can directly influence synaptic plasticity, neurotransmission, and neurodegenerative processes, and have a crucial role in the function and protection of the central nervous system. In fact, it has been observed that the expression of neuronal UCPs significantly decreases in Alzheimer's disease (AD) patients. Here we analyzed the variability of UCP2, -3, -4, and 5 genes in sporadic and familial cases (n = 465) of late-onset AD (LOAD) with respect to healthy controls (n = 442). We showed that a genetic variant in the human UCP4, rs9472817, not only significantly affects the individual susceptibility to LOAD, but also modulates the effect of APOE-ɛ4 on AD risk. In fact, rs9472817-C allele was significantly more frequent in both groups of patients with respect to the control group (p = 6.934*10-4 for familial and p = 1.033*10-3 for sporadic cases). In addition, gene-gene interaction analysis revealed that the effect of APOE-ɛ4 allele on LOAD risk was doubled in homozygote CC subjects; conversely, the risk conferred by the APOE-ɛ4 allele was annulled in subjects with two copies of the G allele. Our findings are further evidence that the efficiency in mitochondrial energy metabolism and oxidative stress are important factors in AD pathogenesis.

%B J Alzheimers Dis %V 51 %P 1265-74 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923023?dopt=Abstract %R 10.3233/JAD-150993 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease. %A Louwersheimer, Eva %A Keulen, M Antoinette %A Steenwijk, Martijn D %A Wattjes, Mike P %A Jiskoot, Lize C %A Vrenken, Hugo %A Teunissen, Charlotte E %A van Berckel, Bart N M %A van der Flier, Wiesje M %A Scheltens, Philip %A van Swieten, John C %A Pijnenburg, Yolande A L %K Aged %K Alzheimer Disease %K Aphasia, Primary Progressive %K Atrophy %K Biomarkers %K Brain %K Female %K Humans %K Language %K Language Tests %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Organ Size %K Positron-Emission Tomography %K Retrospective Studies %X

BACKGROUND: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer's disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences.

OBJECTIVE: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI.

METHODS: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer.

RESULTS: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern.

CONCLUSION: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.

%B J Alzheimers Dis %V 51 %P 581-90 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890751?dopt=Abstract %R 10.3233/JAD-150812 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Homotaurine Effects on Hippocampal Volume Loss and Episodic Memory in Amnestic Mild Cognitive Impairment. %A Spalletta, Gianfranco %A Cravello, Luca %A Gianni, Walter %A Piras, Federica %A Iorio, Mariangela %A Cacciari, Claudia %A Casini, Anna Rosa %A Chiapponi, Chiara %A Sancesario, Giuseppe %A Fratangeli, Claudia %A Orfei, Maria Donata %A Caltagirone, Carlo %A Piras, Fabrizio %K Aged %K Aged, 80 and over %K Analysis of Variance %K Chi-Square Distribution %K Cognitive Dysfunction %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Memory, Episodic %K Mental Status Schedule %K Middle Aged %K Neuroprotective Agents %K Neuropsychological Tests %K Taurine %X

Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances in amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 year. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which was associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI has a positive effect on hippocampus atrophy and episodic memory loss. Future studies should further clarify the mechanisms of its effects on brain morphometry.

%B J Alzheimers Dis %V 50 %P 807-16 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757035?dopt=Abstract %R 10.3233/JAD-150484 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impaired Parahippocampus Connectivity in Mild Cognitive Impairment and Alzheimer's Disease. %A Liu, Jieqiong %A Zhang, Xinqing %A Yu, Chunshui %A Duan, Yunyun %A Zhuo, Junjie %A Cui, Yue %A Liu, Bing %A Li, Kuncheng %A Jiang, Tianzi %A Liu, Yong %K Aged %K Alzheimer Disease %K Apolipoproteins E %K Brain Mapping %K Cognitive Dysfunction %K Female %K Hippocampus %K Humans %K Limbic System %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Neural Pathways %K Rest %K Severity of Illness Index %X

BACKGROUND: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases.

OBJECTIVE: To investigate if disease severity associated altered PHG connectivity in Alzheimer's disease (AD) exists.

METHODS: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson's correlation coefficients between the bilateral PHG and whole brain. Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability.

RESULTS: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini-Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe.

CONCLUSIONS: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD.

%B J Alzheimers Dis %V 49 %P 1051-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599055?dopt=Abstract %R 10.3233/JAD-150727 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors. %A Miwa, Kaori %A Tanaka, Makiko %A Okazaki, Shuhei %A Yagita, Yoshiki %A Sakaguchi, Manabu %A Mochizuki, Hideki %A Kitagawa, Kazuo %K Aged %K Carotid Intima-Media Thickness %K Cerebral Small Vessel Diseases %K Dementia %K Female %K Homocysteine %K Humans %K Incidence %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Predictive Value of Tests %K Proportional Hazards Models %K Risk Factors %K Statistics, Nonparametric %X

BACKGROUND: Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia.

OBJECTIVE: The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors.

METHODS: Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 μmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia.

RESULTS: In the 643 subjects (age: 67.2 ± 8.4 years, male: 59% ; education: 12.9 ± 2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2-13), 47 patients were diagnosed with dementia (Alzheimer's disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE ɛ4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p = 0.043) and the highest tertile of tHcy (HR: 2.50, p = 0.047) for all-cause dementia remained significant.

CONCLUSIONS: Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk.

%B J Alzheimers Dis %V 49 %P 503-13 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484913?dopt=Abstract %R 10.3233/JAD-150458 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Integrating Biomarkers for Underlying Alzheimer's Disease in Mild Cognitive Impairment in Daily Practice: Comparison of a Clinical Decision Support System with Individual Biomarkers. %A Rhodius-Meester, Hanneke F M %A Koikkalainen, Juha %A Mattila, Jussi %A Teunissen, Charlotte E %A Barkhof, Frederik %A Lemstra, Afina W %A Scheltens, Philip %A Lötjönen, Jyrki %A van der Flier, Wiesje M %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Area Under Curve %K Biomarkers %K Cognitive Dysfunction %K Cohort Studies %K Decision Support Systems, Clinical %K Disease Progression %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Outcome Assessment (Health Care) %K Predictive Value of Tests %X

BACKGROUND: Recent criteria allow biomarkers to provide evidence of Alzheimer's disease (AD) pathophysiology. How they should be implemented in daily practice remains unclear, especially in mild cognitive impairment (MCI) patients.

OBJECTIVE: We evaluated how a clinical decision support system such as the PredictAD tool can aid clinicians to integrate biomarker evidence to support AD diagnosis.

METHODS: With available data on demographics, cerebrospinal fluid (CSF), and MRI, we trained the PredictAD tool on a reference population of 246 controls and 491 AD patients. We then applied the identified algorithm to 211 MCI patients. For comparison, we also classified patients based on individual biomarkers (MRI; CSF) and the NIA-AA criteria. Progression to dementia was used as outcome measure.

RESULTS: After a median follow up of 3 years, 72 (34%) MCI patients remained stable and 139 (66%) progressed to AD. The PredictAD tool assigned a likelihood of underlying AD to each patient (AUC 0.82). Excluding patients with missing data resulted in an AUC of 0.87. According to the NIA-AA criteria, half of the MCI patients had uninformative biomarkers, precluding an assignment of AD likelihood. A minority (41%) was assigned to high or low AD likelihood with good predictive value. The individual biomarkers showed best value for CSF total tau (AUC 0.86).

CONCLUSION: The ability of the PredictAD tool to identify AD pathophysiology was comparable to individual biomarkers. The PredictAD tool has the advantage that it assigns likelihood to all patients, regardless of missing or conflicting data, allowing clinicians to integrate biomarker data in daily practice.

%B J Alzheimers Dis %V 50 %P 261-70 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26577521?dopt=Abstract %R 10.3233/JAD-150548 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment. %A Koppara, Alexander %A Wolfsgruber, Steffen %A Kleineidam, Luca %A Schmidtke, Klaus %A Frölich, Lutz %A Kurz, Alexander %A Schulz, Stefanie %A Hampel, Harald %A Heuser, Isabella %A Peters, Oliver %A Reischies, Friedel M %A Jahn, Holger %A Luckhaus, Christian %A Hüll, Michael %A Gertz, Hermann-Josef %A Schröder, Johannes %A Pantel, Johannes %A Rienhoff, Otto %A Rüther, Eckart %A Henn, Fritz %A Wiltfang, Jens %A Maier, Wolfgang %A Jessen, Frank %A Kornhuber, Johannes %A Wagner, Michael %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Phenotype %K Predictive Value of Tests %K Retrospective Studies %K tau Proteins %X

BACKGROUND: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials.

OBJECTIVE: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI).

METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences.

RESULTS: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects.

CONCLUSION: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.

%B J Alzheimers Dis %V 49 %P 547-60 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484902?dopt=Abstract %R 10.3233/JAD-150257 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Linguistic Features Identify Alzheimer's Disease in Narrative Speech. %A Fraser, Kathleen C %A Meltzer, Jed A %A Rudzicz, Frank %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Diagnosis, Computer-Assisted %K Factor Analysis, Statistical %K Female %K Humans %K Language Disorders %K Linguistics %K Logistic Models %K Machine Learning %K Male %K Mental Status Schedule %K Middle Aged %K Narration %K Photic Stimulation %K Speech %K Verbal Behavior %X

BACKGROUND: Although memory impairment is the main symptom of Alzheimer's disease (AD), language impairment can be an important marker. Relatively few studies of language in AD quantify the impairments in connected speech using computational techniques.

OBJECTIVE: We aim to demonstrate state-of-the-art accuracy in automatically identifying Alzheimer's disease from short narrative samples elicited with a picture description task, and to uncover the salient linguistic factors with a statistical factor analysis.

METHODS: Data are derived from the DementiaBank corpus, from which 167 patients diagnosed with "possible" or "probable" AD provide 240 narrative samples, and 97 controls provide an additional 233. We compute a number of linguistic variables from the transcripts, and acoustic variables from the associated audio files, and use these variables to train a machine learning classifier to distinguish between participants with AD and healthy controls. To examine the degree of heterogeneity of linguistic impairments in AD, we follow an exploratory factor analysis on these measures of speech and language with an oblique promax rotation, and provide interpretation for the resulting factors.

RESULTS: We obtain state-of-the-art classification accuracies of over 81% in distinguishing individuals with AD from those without based on short samples of their language on a picture description task. Four clear factors emerge: semantic impairment, acoustic abnormality, syntactic impairment, and information impairment.

CONCLUSION: Modern machine learning and linguistic analysis will be increasingly useful in assessment and clustering of suspected AD.

%B J Alzheimers Dis %V 49 %P 407-22 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484921?dopt=Abstract %R 10.3233/JAD-150520 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer's Disease. %A Sattlecker, Martina %A Khondoker, Mizanur %A Proitsi, Petroula %A Williams, Stephen %A Soininen, Hilkka %A Kłoszewska, Iwona %A Mecocci, Patrizia %A Tsolaki, Magda %A Vellas, Bruno %A Lovestone, Simon %A Dobson, Richard Jb %K Aged %K Alzheimer Disease %K Biomarkers %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Neuropsychological Tests %X

Biomarkers of Alzheimer's disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects.

%B J Alzheimers Dis %V 49 %P 1105-14 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599049?dopt=Abstract %R 10.3233/JAD-140669 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Measuring Information Processing Speed in Mild Cognitive Impairment: Clinical Versus Research Dichotomy. %A Haworth, Judy %A Phillips, Michelle %A Newson, Margaret %A Rogers, Peter J %A Torrens-Burton, Anna %A Tales, Andrea %K Aged %K Aged, 80 and over %K Attention %K Cognitive Dysfunction %K Electroencephalography %K Female %K Humans %K Male %K Mental Processes %K Mental Status Schedule %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Photic Stimulation %K Reaction Time %K Residence Characteristics %X

A substantial body of research evidence is indicative of disproportionately slowed information processing speed in a wide range of multi-trial, computer-based, neuroimaging- and electroencephalography-based reaction time (RT) tests in Alzheimer's disease and mild cognitive impairment (MCI). However, in what is arguably a dichotomy between research evidence and clinical practice, RT associated with different brain functions is rarely assessed as part of their diagnosis. Indeed, often only the time taken to perform a single, specific task, commonly the Trail making test (TMT), is measured. In clinical practice therefore, there can be a failure to assess adequately the integrity of the rapid, serial information processing and response, necessary for efficient, appropriate, and safe interaction with the environment. We examined whether a typical research-based RT task could at least match the TMT in differentiating amnestic MCI (aMCI) from cognitively healthy aging at group level. As aMCI is a heterogeneous group, typically containing only a proportion of individuals for whom aMCI represents the early stages of dementia, we examined the ability of each test to provide intra-group performance variation. The results indicate that as well as significant slowing in performance of the operations involved in TMT part B (but not part A), individuals with aMCI also experience significant slowing in RT compared to controls. The results also suggest that research-typical RT tests may be superior to the TMT in differentiating between cognitively healthy aging and aMCI at group level and in revealing the performance variability one would expect from an etiologically heterogeneous disorder such as aMCI.

%B J Alzheimers Dis %V 51 %P 263-75 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836171?dopt=Abstract %R 10.3233/JAD-150791 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metabolic Syndrome and Mild Cognitive Impairment: A Case-Control Study among Elderly in a Shanghai Suburb. %A Yao, Qian %A Jiang, Guo-Xin %A Zhou, Zhi-Ming %A Chen, Jin-Mei %A Cheng, Qi %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Aging %K Case-Control Studies %K Chi-Square Distribution %K China %K Cities %K Cognition Disorders %K Community Health Planning %K Female %K Humans %K Male %K Mental Status Schedule %K Metabolic Diseases %K Risk Factors %X

BACKGROUND: Metabolic syndrome (MetS) maybe associated with mild cognitive impairment (MCI).

OBJECTIVE: To investigate the relationship between MetS, with its individual or combined components, and MCI among elderly.

METHODS: A case-control study was conducted among the elderly aged 65 years and over in a community located in the southwestern suburb of Shanghai, China. The Chinese version of the Mini-Mental Status Examination (C-MMSE) was used to screen subjects with MCI. Associations of MetS with its individual or combined components and MCI were analyzed using conditional regression analyses with or without adjustment for gender, education, current smoking, current drinking, and physical activities.

RESULTS: There were 379 subjects with MCI and 379 gender- and age-matched healthy controls in the study. Compared with healthy controls in univariate analyses, subjects with MCI were more likely to have less time spent on physical activity, lower C-MMSE score, heavier weight, larger waistline and hipline, higher diastolic blood pressure, higher body mass index, higher abdominal obesity index, higher serum glycated hemoglobin, higher serum triglycerides, higher serum cholesterol, higher serum uric acid, and higher serum alanine aminotransferase. After multivariable adjustment, MetS was significantly associated with an increased risk of MCI (OR = 2.277; 95% CI: 1.086-4.773). Among MetS components, abdominal obesity (OR = 2.101; 95% CI: 1.224-3.608) and hypertension (OR = 2.075; 95% CI: 1.170-3.678) showed a significant association with MCI, respectively; while these two components were combined, the association was stronger (OR = 2.459; 95% CI: 1.360-4.447).

CONCLUSION: MetS and its components, particularly abdominal obesity and hypertension, were found to be significantly associated with the risk of MCI.

%B J Alzheimers Dis %V 51 %P 1175-82 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923017?dopt=Abstract %R 10.3233/JAD-150920 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mindfulness in the Maintenance of Cognitive Capacities in Alzheimer's Disease: A Randomized Clinical Trial. %A Quintana-Hernández, Domingo J %A Miró-Barrachina, María T %A Ibáñez-Fernández, Ignacio J %A Pino, Angelo Santana-Del %A Quintana-Montesdeoca, María P %A Rodríguez-de Vera, Bienvenida %A Morales-Casanova, David %A Pérez-Vieitez, María Del Carmen %A Rodríguez-García, Javier %A Bravo-Caraduje, Noelia %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Cognition Disorders %K Double-Blind Method %K Female %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Mindfulness %K Neuropsychological Tests %K Treatment Outcome %X

BACKGROUND: The Canary Islands longitudinal study on non-pharmacological treatments showed the overall effectiveness of mindfulness in Alzheimer's disease (AD). However, no specific data on the maintenance of cognitive capacities were presented.

OBJECTIVE: To determine whether the practice of mindfulness modifies the course of cognitive impairment in AD.

METHODS:

DESIGN: Longitudinal, non-inferiority and equivalence, randomized clinical trial, repeated-measures design, with three experimental groups and one control group.

PARTICIPANTS: Patients with AD who voluntarily attended the Lidia García Foundation (n = 502). Only those who were treated with donepezil and MMSE ≥18 were included (n = 120).

INTERVENTION: Over a two-year period, each group carried out three weekly sessions of stimulation based on mindfulness, cognitive stimulation therapy, and progressive muscle relaxation.

MEASURES: Cognitive assessment CAMDEX-R (MMSE and CAMCOG).

STATISTICAL ANALYSIS: Repeated-measures ANOVA (p <  0.05) and the effect size Cohen's d were performed.

RESULTS: The mindfulness group showed significant scores compared with the control and muscle relaxation groups (p <  0.05), while mindfulness and cognitive stimulation therapy were equivalent (p≥0.05). Group cognitive stimulation evolved better than the control (p <  0.05) group but not better than the muscle relaxation group (p≥0.05). The effect size compared over two years was large for the mindfulness group (p≥0.80), moderate for the relaxation group (p≥0.50), and low for the cognitive stimulation group (p≥0.20).

CONCLUSION: The practice of mindfulness maintained cognitive function over a period of two years. This longitudinal study suggests that mindfulness can be used as a non-pharmacological treatment to slow cognitive impairment in AD.

%B J Alzheimers Dis %V 50 %P 217-32 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639952?dopt=Abstract %R 10.3233/JAD-143009 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Multimodal Magnetic Resonance Imaging in Alzheimer's Disease Patients at Prodromal Stage. %A Eustache, Pierre %A Nemmi, Federico %A Saint-Aubert, Laure %A Pariente, Jérémie %A Péran, Patrice %K Aged %K Alzheimer Disease %K Biomarkers %K Brain %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Female %K Fluorodeoxyglucose F18 %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Multimodal Imaging %K Neuropsychological Tests %K Organ Size %K Positron-Emission Tomography %K Prodromal Symptoms %K Radiopharmaceuticals %X

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, monitor disease progression, and impact long-term drug analysis. In this study, physiopathological modifications in seven subcortical structures of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) were characterized by simultaneously measuring quantitative magnetic resonance parameters that are sensitive to complementary tissue characteristics (e.g., volume atrophy, shape changes, microstructural damage, and iron deposition). Fourteen MCI patients and fourteen matched, healthy subjects underwent 3T-magnetic resonance imaging with whole-brain, T1-weighted, T2*-weighted, and diffusion-tensor imaging scans. Volume, shape, mean R2*, mean diffusivity (MD), and mean fractional anisotropy (FA) in the thalamus, hippocampus, putamen, amygdala, caudate nucleus, pallidum, and accumbens were compared between MCI patients and healthy subjects. Comparisons were then performed using voxel-based analyses of R2*, MD, FA maps, and voxel-based morphometry to determine which subregions showed the greatest difference for each parameter. With respect to the micro- and macro-structural patterns of damage, our results suggest that different and distinct physiopathological processes are present in the prodromal phase of AD. MCI patients had significant atrophy and microstructural changes within their hippocampi and amygdalae, which are known to be affected in the prodromal stage of AD. This suggests that the amygdala is affected in the same, direct physiopathological process as the hippocampus. Conversely, atrophy alone was observed within the thalamus and putamen, which are not directly involved in AD pathogenesis. This latter result may reflect another mechanism, whereby atrophy is linked to indirect physiopathological processes.

%B J Alzheimers Dis %V 50 %P 1035-50 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836151?dopt=Abstract %R 10.3233/JAD-150353 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Nutritional Status is Associated with Faster Cognitive Decline and Worse Functional Impairment in the Progression of Dementia: The Cache County Dementia Progression Study1. %A Sanders, Chelsea %A Behrens, Stephanie %A Schwartz, Sarah %A Wengreen, Heidi %A Corcoran, Chris D %A Lyketsos, Constantine G %A Tschanz, JoAnn T %K Age of Onset %K Aged, 80 and over %K Alzheimer Disease %K Dementia, Vascular %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Nutritional Status %K Severity of Illness Index %K Sex Factors %K Utah %X

Nutritional status may be a modifiable factor in the progression of dementia. We examined the association of nutritional status and rate of cognitive and functional decline in a U.S. population-based sample. Study design was an observational longitudinal study with annual follow-ups up to 6 years of 292 persons with dementia (72% Alzheimer's disease, 56% female) in Cache County, UT using the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-sb), and modified Mini Nutritional Assessment (mMNA). mMNA scores declined by approximately 0.50 points/year, suggesting increasing risk for malnutrition. Lower mMNA score predicted faster rate of decline on the MMSE at earlier follow-up times, but slower decline at later follow-up times, whereas higher mMNA scores had the opposite pattern (mMNA by time β= 0.22, p = 0.017; mMNA by time2 β= -0.04, p = 0.04). Lower mMNA score was associated with greater impairment on the CDR-sb over the course of dementia (β= 0.35, p <  0.001). Assessment of malnutrition may be useful in predicting rates of progression in dementia and may provide a target for clinical intervention.

%B J Alzheimers Dis %V 52 %P 33-42 %8 2016 02 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967207?dopt=Abstract %R 10.3233/JAD-150528 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patients with Mild Alzheimer's Disease Fail When Using Their Working Memory: Evidence from the Eye Tracking Technique. %A Fernández, Gerardo %A Manes, Facundo %A Politi, Luis E %A Orozco, David %A Schumacher, Marcela %A Castro, Liliana %A Agamennoni, Osvaldo %A Rotstein, Nora P %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Eye Movements %K Female %K Humans %K Linear Models %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Short-Term %K Mental Recall %K Mental Status Schedule %K Predictive Value of Tests %K Semantics %K Verbal Learning %X

Patients with Alzheimer's disease (AD) develop progressive language, visuoperceptual, attentional, and oculomotor changes that can have an impact on their reading comprehension. However, few studies have examined reading behavior in AD, and none have examined the contribution of predictive cueing in reading performance. For this purpose we analyzed the eye movement behavior of 35 healthy readers (Controls) and 35 patients with probable AD during reading of regular and high-predictable sentences. The cloze predictability of words N - 1, and N + 1 exerted an influence on the reader's gaze duration. The predictabilities of preceding words in high-predictable sentences served as task-appropriate cues that were used by Control readers. In contrast, these effects were not present in AD patients. In Controls, changes in predictability significantly affected fixation duration along the sentence; noteworthy, these changes did not affect fixation durations in AD patients. Hence, only in healthy readers did predictability of upcoming words influence fixation durations via memory retrieval. Our results suggest that Controls used stored information of familiar texts for enhancing their reading performance and imply that contextual-word predictability, whose processing is proposed to require memory retrieval, only affected reading behavior in healthy subjects. In AD patients, this loss reveals impairments in brain areas such as those corresponding to working memory and memory retrieval. These findings might be relevant for expanding the options for the early detection and monitoring in the early stages of AD. Furthermore, evaluation of eye movements during reading could provide a new tool for measuring drug impact on patients' behavior.

%B J Alzheimers Dis %V 50 %P 827-38 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836011?dopt=Abstract %R 10.3233/JAD-150265 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patterns of Brain Iron Accumulation in Vascular Dementia and Alzheimer's Dementia Using Quantitative Susceptibility Mapping Imaging. %A Moon, Yeonsil %A Han, Seol-Heui %A Moon, Won-Jin %K Aged %K Aging %K Alzheimer Disease %K Brain %K Brain Mapping %K Cognition %K Dementia, Vascular %K Female %K Humans %K Imaging, Three-Dimensional %K Iron %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Retrospective Studies %K Severity of Illness Index %X

BACKGROUND: Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer's disease (AD) are rarely investigated.

OBJECTIVE: To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM).

MATERIALS AND METHODS: Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this institutional review-board approved study. Susceptibility maps were reconstructed from a three-dimensional multiecho spoiled gradient-echo sequence. Four regions of interest were drawn manually on QSM images, namely the globus pallidus, putamen, caudate nucleus, and pulvinar nucleus of the thalamus. Comparisons of patient demographics, and iron concentrations among the VaD, AD, and control subjects were assessed using analysis of variance and post-hoc analyses. The relationships of age and cognitive state with susceptibility values were assessed using partial correlation analysis.

RESULTS: In VaD and AD, overall susceptibility values were higher than those of control subjects. A significant difference in susceptibility values was found in the putamen and caudate nucleus (p <  0.001 and p = 0.002, respectively). However, susceptibility values did not differ between VaD and AD. Age and cognitive deficit severity were not related to susceptibility values in the VaD and AD groups.

CONCLUSION: Increased iron deposition in the putamen and caudate nucleus in VaD and AD patients was not associated with age or the severity of cognitive deficits. Further evaluations are needed to determine the temporal changes in iron load and their diagnostic role in dementia pathology.

%B J Alzheimers Dis %V 51 %P 737-45 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890777?dopt=Abstract %R 10.3233/JAD-151037 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pauses During Autobiographical Discourse Reflect Episodic Memory Processes in Early Alzheimer's Disease. %A Pistono, Aurélie %A Jucla, Mélanie %A Barbeau, Emmanuel J %A Saint-Aubert, Laure %A Lemesle, Béatrice %A Calvet, Benjamin %A Köpke, Barbara %A Puel, Michèle %A Pariente, Jérémie %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Brain %K Female %K Humans %K Male %K Memory Disorders %K Memory, Episodic %K Mental Status Schedule %K Neuropsychological Tests %K Positron-Emission Tomography %K Statistics as Topic %X

There is a large body of research on discourse production in Alzheimer's disease (AD). Some studies have focused on pause production, revealing that patients make extensive use of pauses during speech. This has been attributed to lexical retrieval difficulties, but pausing may also reflect other forms of cognitive impairment as it increases with cognitive load. The aim of the present study was to analyze autobiographical discourse impairment in AD from a broad perspective, looking at pausing behavior (frequency, duration, and location). Our first objective was to characterize discourse changes in mild cognitive impairment (MCI) due to AD. Our second objective was to determine the cognitive and neuroanatomical correlates of these changes. Fifteen patients with MCI due to AD and 15 matched cognitively normal controls underwent an ecological episodic memory task, a full neuropsychological assessment, and a 3D T1-weighted MRI scans. Autobiographical discourse collected from the ecological episodic memory task was recorded, transcribed, and analyzed, focusing on pausing. Intergroup comparisons showed that although patients did not produce more pauses than controls overall, they did make more between-utterance pauses. The number of these specific pauses was positively correlated with patients' episodic memory performance. Furthermore, neuroimaging analysis showed that, in the patient group, their use was negatively correlated with frontopolar area (BA 10) grey matter density. This region may therefore play an important role in the planning of autobiographical discourse production. These findings demonstrate that pauses in early AD may reflect a compensatory mechanism for improving mental time travel and memory retrieval.

%B J Alzheimers Dis %V 50 %P 687-98 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757034?dopt=Abstract %R 10.3233/JAD-150408 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictive Value of Cerebrospinal Fluid Visinin-Like Protein-1 Levels for Alzheimer's Disease Early Detection and Differential Diagnosis in Patients with Mild Cognitive Impairment. %A Babić Leko, Mirjana %A Borovečki, Fran %A Dejanović, Nenad %A Hof, Patrick R %A Šimić, Goran %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Diagnosis, Differential %K Disease Progression %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neurocalcin %K Peptide Fragments %K Predictive Value of Tests %K ROC Curve %K Statistics as Topic %K tau Proteins %X

Visinin-like protein 1 (VILIP-1) recently emerged as a potential biomarker of Alzheimer's disease (AD). This neuronal calcium sensor protein previously used as a marker of acute ischemic stroke is elevated in the cerebrospinal fluid (CSF) of AD patients. The goal of this study was to assess CSF VILIP-1 potential in early AD diagnosis and in differentiating mild cognitive impairment (MCI) patients with and without risk of AD. Additionally, we tested VILIP-1 ability to differentiate AD from other primary causes of dementia, and predict the progression of AD-related cognitive decline. VILIP-1 levels were compared with five CSF AD biomarkers (t-tau, Aβ1-42, p-tau181, p-tau199, and p-tau231). VILIP-1 successfully differentiated two MCI patient groups characterized by absence or presence of pathological levels of these CSF biomarkers, except for t-tau. VILIP-1/Aβ(1-42) and VILIP-1/p-tau181 ratios also differentiated MCI patients with pathological CSF biomarker levels. However, there was no difference in VILIP-1 levels between AD and MCI patients. VILIP-1/Aβ(1-42) and VILIP-1/p-tau231 ratios reached high sensitivities (above 70%) and very high specificities (above 85%) in differentiating AD patients from HC. Additionally, VILIP-1 differentiated AD from patients with Lewy body disease with 77.1% sensitivity and 100% specificity. VILIP-1 potential as a prognostic biomarker of cognitive decline in AD was also proved since VILIP-1/t-tau, VILIP-1/p-tau181, and VILIP-1/p-tau231 ratios correlated with MMSE scores. These data indicate that VILIP-1 alone or in combination with other AD CSF biomarkers represent a valuable marker for the early diagnosis of AD, recognition of MCI patients at higher risk to develop dementia, and in differentiating AD from LBD.

%B J Alzheimers Dis %V 50 %P 765-78 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836160?dopt=Abstract %R 10.3233/JAD-150705 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictors of Response to Cholinesterase Inhibitors Treatment of Alzheimer's Disease: Date Mining from the TREDEM Registry. %A Gallucci, Maurizio %A Spagnolo, Pierpaolo %A Aricò, Maria %A Grossi, Enzo %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cerebrovascular Disorders %K Cholinesterase Inhibitors %K Female %K Humans %K Life Style %K Male %K Marital Status %K Mental Status Schedule %K Neural Networks (Computer) %K Neuropsychological Tests %K Occupations %K Outpatients %K Prognosis %K Registries %K Treatment Outcome %X

BACKGROUND: The pharmacological treatment of Alzheimer's disease (AD) is based largely on cholinesterase inhibitors (ChEI).

OBJECTIVE: To investigate whether or not some non-pharmacological and contextual factors measured prior to starting treatment such as past occupation, lifestyles, marital status, degree of autonomy and cognitive impairment, living alone or with others, and the degree of brain atrophy are associated with a better response to ChEI treatment.

METHODS: Eighty-four AD and six AD with cerebrovascular disease (AD + CVD) outpatients of Treviso Dementia (TREDEM) Registry, with an average cholinesterase inhibitors treatment length of four years, were considered. The outpatients had undergone a complete evaluation and some non-pharmacological and contextual factors were collected. We defined responder a patient with a delta score T0 - T1 equal or inferior to 2.0 points per year of MMSE and a non-responder a patient with a delta score T0 - T1 superior to 2.0 points per year. In order to identify hidden relationships between variables related to response and non-response, we use a special kind of artificial neural network called Auto-CM, able to create a semantic connectivity map of the variables considered in the study.

RESULTS: A higher cognitive profile, a previous intellectual occupation, healthier lifestyles, being married and not living alone, a higher degree of autonomy, and lower degree of brain atrophy at baseline resulted in affecting the response to long-term ChEI therapy.

CONCLUSION: Non-pharmacological and contextual factors appear to influence the effectiveness of treatment with ChEI in the long term.

%B J Alzheimers Dis %V 50 %P 969-79 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836164?dopt=Abstract %R 10.3233/JAD-150747 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prevalence and Risk Factor of Cognitive Impairment were Different between Urban and Rural Population: A Community-Based Study. %A Tang, Hui-Dong %A Zhou, Yi %A Gao, Xiang %A Liang, Liang %A Hou, Miao-Miao %A Qiao, Yuan %A Ma, Jian-Fang %A Chen, Sheng-Di %K Aged %K Aged, 80 and over %K China %K Cognition Disorders %K Female %K Humans %K Logistic Models %K Male %K Mental Status Schedule %K Middle Aged %K Multivariate Analysis %K Prevalence %K Risk Factors %K Rural Population %K Urban Population %X

BACKGROUND: China is facing a continuously rising numbers of people with cognitive impairment (CI).

OBJECTIVES: To investigate the prevalence and risk factors of CI among elderly people living in rural and urban communities.

METHODS: We conducted a face-to-face survey of CI on 7,900 individuals aged 50 years or older meeting inclusion criteria in the Malu (rural community, n = 4,429) and Wuliqiao (urban community, n = 3,471) communities of Shanghai. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive function. Information on demographic features and potential risk factors for CI was collected during the interview. Multivariate logistic regression was performed to identify risk factors associated with CI.

RESULTS: Based on the education modified MMSE score, we identified 329 CI cases in rural community and 227 in urban community. The prevalence of CI was 7.43% in rural population and 6.54% in urban population (p = 0.13). In the urban population, risk of having CI was associated with age (OR = 1.04; 95% CI: 1.01-1.08), lack of physical activities (OR = 2.25; 95% CI: 1.11-4.57), presence of diabetes mellitus (OR = 1.79; 95% CI: 1.04-3.07), and having three or more children (OR = 2.39; 95% CI: 1.27-4.50). In contrast, factors associated with rural populations included female gender (OR = 2.03; 95% CI: 1.08-3.82), age (OR = 1.06; 95% CI: 1.03-1.08), exposure to pesticides (OR = 4.68; 95% CI: 1.27-17.21), history of encephalitis or meningitis (OR = 6.02; 95% CI: 1.92-18.85) and head trauma (OR = 1.89; 95% CI: 1.10-3.24).

CONCLUSIONS: Urban rural and populations showed different risk factors for CI, suggesting that different preventive strategies in these areas should be performed.

%B J Alzheimers Dis %V 49 %P 917-25 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519443?dopt=Abstract %R 10.3233/JAD-150748 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prognostic Significance of Mild Cognitive Impairment Subtypes for Dementia and Mortality: Data from the NEDICES Cohort. %A Bermejo-Pareja, Félix %A Contador, Israel %A Trincado, Rocío %A Lora, David %A Sánchez-Ferro, Álvaro %A Mitchell, Alex J %A Boycheva, Elina %A Herrero, Alejandro %A Hernández-Gallego, Jesús %A Llamas, Sara %A Villarejo Galende, Alberto %A Benito-León, Julián %K Aged %K Aged, 80 and over %K Algorithms %K Cognitive Dysfunction %K Cohort Studies %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Predictive Value of Tests %K Prognosis %K Proportional Hazards Models %K Spain %X

BACKGROUND: The predictive value of diverse subtypes of mild cognitive impairment (MCI) for dementia and death is highly variable.

OBJECTIVE: To compare the predictive value of several MCI subtypes in progression to dementia and/or mortality in the NEDICES (Neurological Disorders in Central Spain) elderly cohort.

METHODS: Retrospect algorithmic MCI subgroups were established in a non-dementia baseline NEDICES cohort using Spanish adaptations of the original Mini-Mental State Examination (MMSE-37) and Pfeffer's Functional Activities Questionnaire (Pfeffer-11). The presence of MCI was defined according two cognitive criteria: using two cut-offs points on the total MMSE-37 score. Five cognitive domains were used to establish the MCI subtypes. Functional capacity (Pfeffer-11) was preserved or minimally impaired in all MCI participants. The incident dementia diagnoses were established by specialists and the mortality data obtained from Spanish official registries.

RESULTS: 3,411 participants without dementia were assessed in 1994-5. The baseline prevalence of MCI varied according to the MCI definition (4.3%-31.8%). The follow-up was a mean of 3.2 years (1997-8). The dementia incidence varied between 14.9 and 71.8 per 1,000/person-years. The dementia conversion rate was increased in almost all MCI subgroups (p >  0.01), and mortality rate was raised only in four MCI subtypes. The amnestic-multi-domain MCI (aMd-MCI) had the best dementia predictive accuracy (highest positive likelihood ratio and highest clinical utility when negative).

CONCLUSIONS: Those with aMd-MCI were at greatest risk of progression to dementia, as in other surveys and might be explored with increased attention in MCI research and in dementia preventive trials.

%B J Alzheimers Dis %V 50 %P 719-31 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757038?dopt=Abstract %R 10.3233/JAD-150625 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reduction of Amyloid-β Plasma Levels by Hemodialysis: An Anti-Amyloid Treatment Strategy? %A Tholen, Susanne %A Schmaderer, Christoph %A Chmielewski, Stefan %A Förstl, Hans %A Heemann, Uwe %A Baumann, Marcus %A Steubl, Dominik %A Grimmer, Timo %K Adult %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Cognition Disorders %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Renal Dialysis %X

BACKGROUND: Cognitive impairment in hemodialysis patients is common, but the underlying pathogenesis remains unclear. Alzheimer's disease is the most common cause of dementia in the general elderly population. Histopathological hallmarks are, among others, senile plaques, which consist of amyloid-β (Aβ).

OBJECTIVE: To measure plasma levels of Aβ42 and Aβ40 during hemodialysis and to examine potential associations with cognitive performance in cognitively impaired hemodialysis patients.

METHODS: Plasma samples of 26 hemodialysis patients were collected shortly before, after 50% of dialysis time, and at the end of a dialysis session. Aβ42 and Aβ40 levels were measured by a high-sensitivity ELISA for human amyloid-β. Cognition was tested under standardized conditions using the Montreal Cognitive Assessment (MoCA) as proposed previously.

RESULTS: Clearance rates of both peptides during one dialysis session were 22% and 35% for Aβ42 and Aβ40, respectively. Aβ42 but not Aβ40 baseline levels were significantly associated with MoCA test results (r = 0.654, p = 0.001).

CONCLUSION: In cognitively impaired hemodialysis patients plasma Aβ42 levels were associated with cognitive performance and both Aβ42 and Aβ40 plasma levels could be effectively reduced by dialysis. By inducing peripheral Aβ sink, hemodialysis may be considered as an anti-amyloid treatment strategy.

%B J Alzheimers Dis %V 50 %P 791-6 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682683?dopt=Abstract %R 10.3233/JAD-150662 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reversible Mild Cognitive Impairment: The Role of Comorbidities at Baseline Evaluation. %A Grande, Giulia %A Cucumo, Valentina %A Cova, Ilaria %A Ghiretti, Roberta %A Maggiore, Laura %A Lacorte, Eleonora %A Galimberti, Daniela %A Scarpini, Elio %A Clerici, Francesca %A Pomati, Simone %A Vanacore, Nicola %A Mariani, Claudio %K Analysis of Variance %K Cognitive Dysfunction %K Cohort Studies %K Comorbidity %K Female %K Humans %K Male %K Memory %K Mental Status Schedule %K Neuropsychological Tests %K Reference Values %K Verbal Learning %X

The prognostic value of mild cognitive impairment (MCI) is being questioned, with some MCI subjects reverting to normal cognition (NC). The reversion rate varies mostly depending on the study design, the setting, and both MCI and NC definitions. Previous studies have focused on the profile of subjects who revert to NC, but the role of comorbidities has not been entirely investigated. We aimed to evaluate the proportion of MCI subjects who revert to NC in a memory clinic context, focusing on the role of comorbidities. Between 2004 and 2013, 374 MCI subjects were recruited. During a mean time of 32 ± 25.5 months, 21 subjects (5.6%) reverted to NC. Subjects who reverted to NC were younger (p = 0.0001), more educated (p = 0.0001), had a better global cognition (p = 0.0001), as assessed by the Mini-Mental State Examination (MMSE) and suffered from more comorbidities (p = 0.002), as assessed by Cumulative Illness Rating Scale (CIRS) than those who developed dementia. The Cox Regression Model, constructed to adjust for the confounders, showed that the higher were the MMSE (HR = 1.83, CI 95%: 1.07-3.11) and the CIRS score (HR = 1.3, CI 95% 0.88-1.92) at baseline, the higher was the probability of returning to NC than developing dementia, though the last association was not significant. Subjects who reverted to NC were more frequently affected by respiratory (p = 0.002), urologic (p = 0.012), and psychiatric (p = 0.012) diseases. The cognitive performance of subjects with medical comorbidities could benefit from preventive strategies aimed at treating the underlying diseases.

%B J Alzheimers Dis %V 51 %P 57-67 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836169?dopt=Abstract %R 10.3233/JAD-150786 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Alzheimer's and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer's Disease. %A Gavett, Brandon E %A John, Samantha E %A Gurnani, Ashita S %A Bussell, Cara A %A Saurman, Jessica L %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Apolipoproteins E %K Cerebrovascular Disorders %K Continental Population Groups %K Dementia %K Educational Status %K Female %K Genotype %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Models, Theoretical %X

BACKGROUND: Dementia severity can be modeled as the construct δ, representing the "cognitive correlates of functional status."

OBJECTIVE: We recently validated a model for estimating δ in the National Alzheimer's Coordinating Center's Uniform Data Set; however, the association of δ with neuropathology remains untested.

METHODS: We used data from 727 decedents evaluated at Alzheimer's Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants' last visit prior to death were used to estimate dementia severity (δ).

RESULTS: A structural equation model using age, education, race, and apolipoprotein E (APOE) genotype (number of ɛ2 and ɛ4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more ɛ2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more ɛ4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD.

CONCLUSIONS: Using δ as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity.

%B J Alzheimers Dis %V 49 %P 531-45 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444761?dopt=Abstract %R 10.3233/JAD-150252 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Self-Consciousness in Patients with Behavioral Variant Frontotemporal Dementia. %A Arroyo-Anlló, Eva M %A Bouston, Adèle Turpin %A Fargeau, Marie-Noëlle %A Orgaz Baz, Begõna %A Gil, Roger %K Aged %K Brain %K Educational Status %K Female %K Frontotemporal Dementia %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Positron-Emission Tomography %K Psychological Tests %K Self Concept %X

Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The medial prefrontal cortex may play a critical role in SC. The main aim of this paper was to examine SC in patients with behavioral variant frontotemporal dementia, who are characterized more by changes in personal, social, and emotional conduct and loss of insight than by cognitive disturbances. Control and patient groups of 21 subjects each, matched by age, educational level, gender, and nationality were assessed using a SC questionnaire. It measures several aspects: Personal identity, Anosognosia, Affective state, Body representation, Prospective memory, Introspection, and Moral judgments. The most disturbed ones in patients were Anosognosia, Affective state, and Moral judgments, and the least disturbed aspects were awareness of identity and of body representation. No significant correlations were found between the SC score and any clinical or demographical characteristics. The core deficiency of SC in patients was related to behavioral SC aspects, which are more dependent on orbito-frontal functioning.

%B J Alzheimers Dis %V 49 %P 1021-9 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599058?dopt=Abstract %R 10.3233/JAD-150821 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of the Spanish version of the Baylor Profound Mental Status Examination. %A Salmerón, Sergio %A Huedo, Isabel %A López-Utiel, Melisa %A Soler-Moratalla, Isabel %A Flores-Ruano, Teresa %A Fernández-Sánchez, Miguel %A Noguerón, Alicia %A Doody, Rachelle S %A Abizanda, Pedro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Cognition Disorders %K Female %K Humans %K Language %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Reproducibility of Results %K Severity of Illness Index %K Spain %X

BACKGROUND: There are no short valid instruments to evaluate cognitive status in severe Alzheimer's disease (AD) patients in the Spanish language.

OBJECTIVE: To validate the Spanish version of the Baylor Profound Mental Status Examination (BPMSE-Sp).

METHODS: The Baylor Profound Mental Status Examination (BPMSE) was translated to Spanish and back translated. Validation was conducted in 100 patients with severe probable AD with a Mini-Mental State Examination (MMSE) <12. We assessed internal consistency (Cronbach's alpha), concurrent validity (Pearson's correlations) with the MMSE, Severe Impairment Battery (SIB), Neuropsychiatric Inventory Short Form (NPI-Q) and the Functional Assessment Staging and reliability.

RESULTS: The mean age of patients was 84.9; 74% were female; 64% were institutionalized. The mean MMSE was 5.6; the mean BPMSE-Sp was 13.6; the mean BPMSE-Sp behavior was 1.2; the mean SIB was 42.2; and the mean NPI-Q was 4.7. BPMSE-Sp presented good internal consistency (Cronbach α= 0.84). There were significant correlations between the BPMSE-Sp and MMSE (r = 0.86, p <  0.001), and between the BPMSE-Sp and SIB (r = 0.92, p <  0.001). Inter-rater and test-retest reliability were in both cases excellent, ranging between 0.96 and 0.99 (p <  0.001). BPMSE-Sp had fewer floor and ceiling effects than the MMSE.

CONCLUSIONS: The BPMSE-Sp is a valid tool for use in daily practice and research in the evaluation of cognitive function of patients with severe AD.

%B J Alzheimers Dis %V 49 %P 73-8 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444781?dopt=Abstract %R 10.3233/JAD-150422 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vascular Health Indices and Cognitive Domain Function: Singapore Longitudinal Ageing Studies. %A Lim, Shir Lynn %A Gao, Qi %A Nyunt, Ma Shwe Zin %A Gong, Lingli %A Lunaria, Josephine B %A Lim, May Li %A Ling, Audrey %A Lam, Carolyn Su-Ping %A Richards, Arthur Mark %A Ling, Lieng Hsi %A Ng, Tze Pin %K Aged %K Blood Flow Velocity %K Blood Pressure %K Cardiovascular Diseases %K Carotid Intima-Media Thickness %K Cognitive Aging %K Female %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Singapore %K Vascular Stiffness %X

BACKGROUND: Few studies have comprehensively evaluated the relationship between vascular disease and cognition of older adults without cardiac disease.

OBJECTIVE: We explored the associations of structural atherosclerosis, vascular stiffness, and reactivity with global, memory, attention, language, visuospatial ability, and executive function in community-dwelling, non-demented older Asians without cardiac diseases.

METHODS: Cognition was assessed by Mini-Mental State Examination (MMSE) (n = 308) and detailed neuropsychological tests (n = 155). Vascular measures included carotid intima-media thickness; aortic stiffness [carotid-femoral pulse wave velocity (CFPWV), aortic augmentation index (AI), and aortic pulse pressure (PP)]; carotid stiffness [elasticity modulus (Ep), beta index (β), arterial compliance (AC), carotid AI]; and endothelial function [reactive hyperemia index (RHI)]. Multivariable analyses controlled for potential confounding by demographics, apolipoprotein E genotype and cardiovascular risk factors.

RESULTS: The participants' mean age was 63.0 ± 6.1 years. Inverse associations with MMSE were found for AC (β= 0.128, p = 0.019), Ep (β= -0.151, p = 0.008), β index (β= -0.122, p = 0.029), carotid stiffness z-score (β= -0.154, p = 0.007); with executive function for CFPWV (β= -0.209, p = 0.026), AC (β= 0.214, p = 0.005), Ep (β= -0.160, p = 0.050), β index (β= -0.165, p = 0.041), and both aortic (β= -0.229, p = 0.010) and carotid (β= -0.208, p = 0.010) stiffness z-scores; with verbal memory for AI (β= -0.229, p = 0.004) and aortic (β= -0.263, p = 0.004) stiffness z-score; with language for AI (β= -0.155, p = 0.025), aortic stiffness z-score (β= -0.196, p = 0.011). RHI positively correlated with visuospatial ability (β= 0.195, p = 0.013) and executive function (β= 0.151, p = 0.045).

CONCLUSION: The results support a link between systemic vascular health and neurocognitive function in older Asian adults. Subclinical noninvasive measures of arterial stiffness and reactivity may identify individuals vulnerable to cognitive impairment.

%B J Alzheimers Dis %V 50 %P 27-40 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639958?dopt=Abstract %R 10.3233/JAD-150516 %0 Journal Article %J J Alzheimers Dis %D 2016 %T White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer's Disease. %A Sánchez-Valle, Raquel %A Monté, Gemma C %A Sala-Llonch, Roser %A Bosch, Beatriz %A Fortea, Juan %A Lladó, Albert %A Antonell, Anna %A Balasa, Mircea %A Bargalló, Nuria %A Molinuevo, José Luis %K Adult %K Aging %K Alzheimer Disease %K Brain %K Cohort Studies %K Diffusion Tensor Imaging %K Disease Progression %K Family %K Female %K Heterozygote %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Mutation %K Neuropsychological Tests %K Organ Size %K Presenilin-1 %K White Matter %X

PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer's disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p <  0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p <  0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease; thus DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease.

%B J Alzheimers Dis %V 51 %P 827-35 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923015?dopt=Abstract %R 10.3233/JAD-150899 %0 Journal Article %J J Alzheimers Dis %D 2016 %T White Matter and Hippocampal Volume Predict the Risk of Dementia in Patients with Cerebral Small Vessel Disease: The RUN DMC Study. %A van Uden, Ingeborg W M %A van der Holst, Helena M %A Tuladhar, Anil M %A van Norden, Anouk G W %A de Laat, Karlijn F %A Rutten-Jacobs, Loes C A %A Norris, David G %A Claassen, Jurgen A H R %A van Dijk, Ewoud J %A Kessels, Roy P C %A de Leeuw, Frank-Erik %K Aged %K Cerebral Small Vessel Diseases %K Cohort Studies %K Dementia %K Diffusion Tensor Imaging %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Statistics, Nonparametric %K White Matter %X

BACKGROUND: The relationship between cerebral small vessel disease (SVD) and dementia has been studied without considering white matter (WM) volume, the microstructural integrity of the WM surrounding the SVD, and grey matter (GM).

OBJECTIVE: We prospectively investigated the relationship between these structures and the risk of dementia, and formed a prediction model to investigate which characteristics (macro- or microstructural) explained most of the variance.

METHODS: The RUN DMC study is a prospective cohort study among 503 non-demented participants with an age between 50 and 85 years at baseline, with baseline assessment in 2006 and follow-up assessment in 2012. Two were lost to follow-up (yielding a 99.6% response-rate). Cox regression analysis was used, to calculate hazard ratios for dementia, of baseline MRI characteristics. Tract-Based Spatial Statistics (TBSS) analysis was used to assess the added value of microstructural integrity of the WM.

RESULTS: Mean age at baseline was 65.6 years (SD 8.8) and 56.8% was male. 43 participants developed dementia (8.6%), resulting in a 5.5-year cumulative risk of 11.1% (95% CI 7.7-14.6). Low WM and hippocampal volume are significant predictors for dementia. WM, WM hyperintensities, and hippocampal volume explained most of the variance. TBSS analyses showed no additional value of diffusion parameters.

CONCLUSIONS: WM and hippocampal volume were the main predictors for the development of incident dementia at 5-year follow-up in elderly with SVD. There was no additional diagnostic value of the diffusion tensor imaging parameters on top of the macrostructural characteristics.

%B J Alzheimers Dis %V 49 %P 863-73 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26529206?dopt=Abstract %R 10.3233/JAD-150573 %0 Journal Article %J J Alzheimers Dis %D 2016 %T White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer's Disease. %A Coutu, Jean-Philippe %A Goldblatt, Alison %A Rosas, H Diana %A Salat, David H %K Aged %K Aging %K Alzheimer Disease %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Factor Analysis, Statistical %K Female %K Hippocampus %K Humans %K Imaging, Three-Dimensional %K Male %K Mental Status Schedule %K Neuropsychological Tests %K White Matter %X

White matter lesions are highly prevalent in individuals with Alzheimer's disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimer's Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.

%B J Alzheimers Dis %V 49 %P 329-42 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444767?dopt=Abstract %R 10.3233/JAD-150306 %0 Journal Article %J J Alzheimers Dis %D 2016 %T δ Scores are Exportable Across Cultural and Linguistic Boundaries. %A Royall, Donald R %A Palmer, Raymond F %A Matsuoka, Teruyuki %A Kato, Yuka %A Taniguchi, Shogo %A Ogawa, Mayu %A Fujimoto, Hiroshi %A Okamura, Aiko %A Shibata, Keisuke %A Nakamura, Kaeko %A Nakaaki, Shutaro %A Koumi, Hiroyuki %A Mimura, Masaru %A Fukui, Kenji %A Narumoto, Jin %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Cognitive Dysfunction %K Cohort Studies %K Culture %K Executive Function %K Female %K Humans %K Linguistics %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Psychometrics %K Reproducibility of Results %K ROC Curve %K Texas %X

The latent variable "δ", can accurately diagnose dementia. Its generalizability across populations is unknown. We constructed a δ homolog ("dT2J") in data collected by the Texas Alzheimer's Research and Care Consortium (TARCC). From this, we calculated a composite d-score "d". We then tested d's generalizability across random subsets of TARCC participants and to a convenience sample of elderly Japanese persons with normal cognition (NC), mild cognitive impairment (MCI), and dementia (AD) (n = 176). dT2J was indicated by Instrumental Activities of Daily Living and psychometric measures. Embedded in this battery were the Mini-Mental Status Examination (MMSE) and an executive clock-drawing task (CLOX). Only MMSE and CLOX were available in both TARCC and the Japanese cohort. Therefore, a second composite variable, "T2J", was constructed solely from the factor loadings of CLOX and MMSE on d. The diagnostic accuracy of T2J was estimated in the validation sample, the remainder of the TARCC cohort, and in the Japanese sample. The areas under the receiver operating curve (AUC; ROC) for T2J were compared in each sample, and against d in TARCC. The AUCs for T2J were statistically indiscriminable within TARCC, and in Japanese persons. In Japanese persons, AUCs for T2J were 0.97 for the discrimination between AD versus NC, 0.86 for AD versus MCI, and 0.79 for NC versus MCI. The AUCs for T2J in Japanese persons were higher than any individual psychometric measure in that sample. Valid d-score composites can be abstracted from a subset of δ's indicators. Moreover, those composites are exportable across cultural and linguistic boundaries.

%B J Alzheimers Dis %V 49 %P 561-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444764?dopt=Abstract %R 10.3233/JAD-150261 %0 Journal Article %J Ann Neurol %D 2012 %T An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease. %A Jack, Clifford R %A Knopman, David S %A Weigand, Stephen D %A Wiste, Heather J %A Vemuri, Prashanthi %A Lowe, Val %A Kantarci, Kejal %A Gunter, Jeffrey L %A Senjem, Matthew L %A Ivnik, Robert J %A Roberts, Rosebud O %A Rocca, Walter A %A Boeve, Bradley F %A Petersen, Ronald C %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Aniline Compounds %K Biomarkers %K Brain %K Cognition Disorders %K Disease Progression %K Female %K Fluorodeoxyglucose F18 %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K National Institute on Aging (U.S.) %K Neuropsychological Tests %K Positron-Emission Tomography %K Thiazoles %K United States %X

OBJECTIVE: A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines.

METHODS: We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria.

RESULTS: The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non-AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP.

INTERPRETATION: This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1-3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important.

%B Ann Neurol %V 71 %P 765-75 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22488240?dopt=Abstract %R 10.1002/ana.22628 %0 Journal Article %J Neurology %D 2011 %T Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. %A Li, J %A Wang, Y J %A Zhang, M %A Xu, Z Q %A Gao, C Y %A Fang, C Q %A Yan, J C %A Zhou, H D %K Aged %K Alzheimer Disease %K Cerebrovascular Disorders %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Incidence %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptides %K Regression Analysis %K Residence Characteristics %K Retrospective Studies %K Risk Factors %K Statistics, Nonparametric %X

OBJECTIVE: Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia.

METHODS: A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion.

RESULTS: At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion.

CONCLUSION: VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.

%B Neurology %V 76 %P 1485-91 %8 2011 Apr 26 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/21490316?dopt=Abstract %R 10.1212/WNL.0b013e318217e7a4